N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals

ABSTRACT

The present invention relates to N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides of the formula (I), (R2)n wherein Ar, R1, R2 and n have the meanings indicated in the claims. The compounds of the formula (I) are valuable pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK), in particular of serum and glucocorticoid regulated kinase isoform 1 (SGK-1, SGK1), and are suitable for the treatment of diseases in which SGK activity is inappropriate, for example degenerative joint disorders or inflammatory processes such as osteoarthritis or rheumatism. The invention furthermore relates to processes for the preparation of the compounds of the formula (I), their use as pharmaceuticals, and pharmaceutical compositions comprising them.

The present invention relates toN-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides of theformula I,

wherein Ar, R1, R2 and n have the meanings indicated below. Thecompounds of the formula I are valuable pharmacologically activecompounds which modulate protein kinase activity, specifically theactivity of serum and glucocorticoid regulated kinase (SGK), inparticular of serum and glucocorticoid regulated kinase isoform 1(SGK-1, SGK1), and are suitable for the treatment of diseases in whichSGK activity is inappropriate, for example degenerative joint disordersor inflammatory processes such as osteoarthritis or rheumatism. Theinvention furthermore relates to processes for the preparation of thecompounds of the formula I, their use as pharmaceuticals, andpharmaceutical compositions comprising them.

Due to their physiologic importance, variety, and ubiquity, proteinkinases have become one of the most important and widely-studied familyof enzymes in biochemical and medical research. Currently, there areabout 500 different known protein kinases. However, because three tofour percent of the human genome is a code for the formation of proteinkinases, there may be many thousands of distinct and separate kinases inthe human body. Protein kinases serve to catalyze the phosphorylation ofan amino acid side chain in various proteins by the transfer of thegamma-phosphate of the ATP-Mg²⁺ complex to said amino acid side chain.These enzymes control the majority of the signaling processes insidecells, thereby governing cell function, growth, differentiation anddestruction (apoptosis) through reversible phosphorylation of thehydroxyl groups of serine, threonine and tyrosine residues in proteins.Studies have shown that protein kinases are key regulators of many cellfunctions, including signal transduction, transcriptional regulation,cell motility, and cell division. Several oncogenes have also been shownto encode protein kinases, suggesting that kinases play a role inoncogenesis. These processes are highly regulated, often by complexintermeshed pathways where each kinase will itself be regulated by oneor more kinases. Consequently, aberrant or inappropriate protein kinaseactivity can contribute to the rise of disease states associated withsuch aberrant kinase activity.

The protein kinase family of enzymes is typically classified into twomain subfamilies, protein tyrosine kinases, which phosphorylate tyrosineresidues, and protein serine/threonine kinases (PSTK), whichphosphorylate serine and threonine residues. The PSTK subfamily includescyclic AMP- and cyclic GMP-dependent protein kinases, calcium- andphospholipid-dependent protein kinase, calcium- and calmodulin-dependentprotein kinases, casein kinases, cell division cycle protein kinases andothers. These kinases are usually cytoplasmic or associated with theparticulate fractions of cells, possibly by anchoring proteins. Aberrantprotein serine/threonine kinase activity has been implicated or issuspected in a number of pathologies such as rheumatoid arthritis,psoriasis, septic shock, bone loss, many cancers and other proliferativediseases. Accordingly, serine/threonine kinases and their associatedsignal transduction pathways are important targets for drug design.

Serum and glucocorticoid regulated kinases, also designated asserum/glucocorticoid regulated kinase, serum and glucocorticoid inducedkinase, serum and glucocorticoid inducible kinase or serum andglucocorticoid dependent kinase, form a family of serine/threoninekinases. Currently three members are known, designated as SGK-1, SGK-2and SGK-3. SGK-3 is also described under the name SGKL (SGK-like), andCISK. SGK-1 was described in 1993 for the first time as an “immediateearly genes” in a rat mammary cancer cell line (Webster et al., 1993a;Webster et al., 1993b). At the protein level the three isoforms show ahomology of at least 80% in their catalytic domain. SGK-1 is expressedin almost all tissues that have been tested so far, but the amounts ofmRNA expressed vary greatly depending on the nature of the studiedtissue type (Gonzalez-Robayna et al., 1999; Waldegger et al., 1999;Alliston et al., 2000; Klingel et al., 2000; Lang et al., 2000; Loffinget al., 2001; Fillon et al., 2002; Warntges et al., 2002a). In addition,SGK-1 mRNA is found in several embryonic tissues. During mouseembryogenesis, the SGK-1 mRNA shows development-dynamic changes inspecific tissues of the embryo (decidua, yolk sac, otic vesicle), and isdetectable during the organogenesis in lung buds, brain, heart, liver,thymus, etc. (Lee et al., 2001). SGK-2 is expressed with greatestabundance in epithelial tissues, such as in the kidney, liver, pancreas,and specific areas of the brain (Kobayashi et al., 1999). SGK-3 wasdetected in all tested tissues and is especially found in the adultheart and spleen (Kobayashi et al., 1999; Liu et al., 2000).

A distinguishing feature of SGK to many other kinases is based on thestringent stimulus-dependent regulation of transcription, cellularlocalization and enzymatic activation (Firestone et al., 2003) of themolecule. In order to induce and activate SGK-1, a variety of stimuliare known. These include mineralocorticoids (Brennan and Fuller, 2000;Shigaev et al., 2000; Bhargava et al., 2001), gonadotropins (Richards etal., 1995; Gonzalez-Robayna et al., 2000), 1,25(OH)2D3 (Akutsu et al.,2001), p 53, osmotic, hypotonic and cellular volume changes (Waldeggeret al., 1997; Klingel et al., 2000; Waldegger et al., 2000; Rozansky etal., 2002; Warntges et al., 2002a), cytokines such as GM-CSF andTNF-alpha (Cooper et al., 2001) or by TGF-beta (Kumar et al., 1999;Waldegger et al.; 1999; Lang et al., 2000). In further growth-dependentsignaling pathways SGK is induced by serum (Webster et al., 1993a),insulin and IGF-1 (Kobayashi and Cohen, 1999; Park et al., 1999;Perrotti et al., 2001), FSH (Alliston et al., 1997), Fibroblast andPlatelet-derived growth factor (Davies et al., 2000), activators of theErk signaling cascade (Hayashi et al., 2001) and TPA (Mizuno andNishida, 2001). SGK-1 is also known to be activated in pathologicalchanges such as ischemic brain injury (Imaizumi et al., 1994), viralhepatitis (Fillon et al., 2002), pulmonary fibrosis (Warntges et al.,2002b) or cardiac fibrosis (Funder 2001).

In order to be converted into its functional form, SGK-1 requiresactivation by phosphorylation. This is mediated by a signaling cascadeinvolving the phosphatidylinositol 3 (PI-3) kinase and phosphoinositide3-dependent kinases PDK1 and PDK2. The activation of SGK-1 through thePI-3 kinase signaling pathway is known to be a response to insulin, IGFand growth factors. For activation the phosphorylation of two amino acidresidues is necessary, threonine²⁵⁶ on the T-loop and serine⁴²² at thehydrophobic motif of the protein. Phosphorylation at threonine²⁵⁶ ismediated by PDK1, phosphorylation at serine⁴²² should be catalyzed by aputative PDK2, which is not yet known (Kobayashi and Cohen, 1999; Parket al., 1999; Biondi et al., 2001).

For the function of SGK, there are a series of studies that showregulatory influence of SGK-1, SGK-2 and SGK-3 on cell membranechannels. It was shown that the epithelial Na⁺ channel (ENaC), the maintransporter for the mineralocorticoid-regulated Na⁺ reabsorption in therenal tubule, is a target of SGK-1, SGK-2 and SGK-3 (Alvarez de la Rosaet al., 1999; Böhmer et al., 2000; Wagner et al, 2001; Wang et al.,2001; Faletti et al., 2002; Friedrich et al., 2003). The interaction ofENaC and SGK is not by direct phosphorylation (Lang et al., 2000), butdue to the inactivation of the ubiquitin ligase Nedd-4-2 (Debonnevilleet al., 2001; Snyder et al., 2002) as a result of phosphorylation bySGK. As a result, the amount and residence time of ENaC in the cellmembrane is increased (Staub et al., 1997; Alvarez de la Rosa et al.,1999; Wagner et al., 2001). It has also been shown in a number ofexperiments that ROMK1 is a molecular target of SGK. However, ROMK1 isnot directly regulated by SGK, but needs the “Na⁺/H⁺ exchange regulatingfactor 2” (NHERF2) as an intermediary molecule (Shenolikar and Weinmann,2001; Yun, 2003). The same mechanism applies to another target moleculeof SGK, the Na⁴YH⁺ transporter NHE3 (Yun et al., 2002). In addition ithas also been shown in experiments on Xenopus oocytes that SGKinfluences the Kv1.3 channel-dependent K⁺ current (Gamper et al., 2002;Warntges et al., 2002a). It was also reported that SGK regulates theamino acid transporter SN1 and 42F/LAT (Wagner et al., 2000; Böhmer etal., 2003a, b). SGK-1 has also been shown to play a role in cellproliferation and electrolyte homeostasis (Loffing et al., 2006;McCormick et al., 2005; Vallon et al., 2005; Vallon and Lang, 2005; Langet al., 2003). SGK-1 is thought to regulate several cellular mechanismsthat contribute to disease states. For example, SGK-1 has been shown tomediate fibronectin formation in diabetic nephropathy (Feng et al.,2005). SGK1 has also been shown to mediate insulin, IGF-1, andaldosterone-induced Na⁺ retention in renal and cardiovascular disease(McCormick et al., 2005; Vallon et al., 2005; Lang et al., 2003). Inaddition, SGK-1 has been shown to be involved in inducing thetranscription and procoagulation activity of tissue factor (TF) (BelAibaet al., 2006), and in regulating IGF-1-mediated cell proliferation(Henke et al., 2004).

Osteoarthritis (OA) is one of the most common degenerative jointdiseases and leads in an advanced stage to a loss of joint function.During the chronic course of illness, there is a destruction of thearticular cartilage down to the underlying bone tissue, which makes ajoint replacement surgery in affected patients necessary. In addition tothe destruction of the cartilage, pathological changes in the synovialmembrane and the ligaments can also be observed. The disease istemporarily accompanied by inflammatory processes like in rheumatoidarthritis, but differs from it. The exact causes of the disease arestill unknown, however, several factors come into question, such asmetabolic changes, mechanical stress, genetic disorders or jointinjuries. Regardless of the original trigger, the degradation ofarticular cartilage occurs as a common pathological feature of OA. A keyfeature of the pathological condition of OA is the proteolytic cleavageof collagens and proteoglycans. Simultaneously a number of otherprocesses occur such as anabolic repair mechanisms redifferentiation ofthe cells or cell death. The precise molecular mechanisms underlyingthese processes are still poorly understood.

The healthy functioning of the adult cartilage is created by its uniquebiomechanical properties, providing both the resistance against highpressure as well as the necessary elasticity of the tissue. The decisivefactor is the special organization of the cartilage tissue. Unlike mostother tissues, the cartilage cells are not in direct contact but areembedded separately from each other in an extracellular matrix (ECM).The macromolecules of this ECM guarantee the viability of the articularcartilage and joints. The basic structure of the ECM consists of anetwork that is formed by fibrils of collagen types II, IX and XI.Proteoglycans, mainly aggrecan, are embedded in the ECM producing anextremely high osmotic water binding capacity. The water pressuregenerated in connection with the properties of the collagen backboneguarantee the specific properties of the cartilage. A main feature ofthe pathogenesis of OA is the loss of the ECM of the cartilage and thearticular cartilage tissue. The function of the affected joint isrestricted by or lost by this mechanism. In addition, varioussymptomatic parameters such as pain appear during symptomaticprogression of the disease. Current treatments for osteoarthritis arelimited mostly to the alleviation of symptomatic complaints. A causaltherapy based on drugs, which leads to the decrease of cartilagedegeneration, is not possible to current knowledge. Therefore, there isa considerable need for novel drugs for the prevention and/or therapy ofosteoarthritis.

It has been shown, through comparative gene expression analysis ofsamples of total-cellular RNA from healthy and degenerated/degeneratingcartilage that SGK-1 is expressed in degenerated/degeneratingosteoarthritic cartilage, while it is not detectable in healthyarticular cartilage (Bartnik et al., 2006). Moreover, furtherexperiments gave evidence of the causal implication of SGK in thepathogenesis of degenerative cartilage changes (Bartnik et al., 2006).As a conclusion of these studies, SGK-1 is specifically involved inpathological conditions of the cartilage, for example in the context ofrheumatoid arthritis or osteoarthritis, in particular in the context ofosteoarthritis, and thus represents a key molecule inducing cartilagedegradative processes. Due to the high homology between the SGK familymembers, it is assumed that this also applies to the SGK-2 and SGK-3.

The identification of these relationships allows the discovery of drugsfor the prevention or therapy of degenerative cartilage changes bydetermining the effect of potential drugs on the activity of SGK and/orthe levels of SGK by known test methods. The causal implication of SGKin the pathogenesis of degenerative joint disease allows a focusedsearch for therapeutic agents that target regulatory mechanisms for therestoration of normal cell physiology of cartilage. In the joints ofmouse embryos SGK-1 mRNA was detected specifically in hypertrophicchondrocytes but not in proliferative cells. The role of SGK-1 in thismodel of skeletal development and endochondral ossification shows thatthe natural occurrence of SGK-1 in cartilage is not associated with thesynthesis and maintenance of cartilage, but exerts its function in theconversion (hypertrophy) and degradation. The expression of SGK-1 inosteoarthritic cartilage is thus a process that causes or promotes thepathology of OA. Due to its regulatory properties SGK-1 could be a keymolecule for the induction of early pathological changes in cartilage aswell as for the later degradative activities. Therefore, SGK-1 is a veryrelevant target for the pharmacological intervention in osteoarthritis.

To specifically study the function of SGK-1 during differentiation ofcartilage, human SGK-1 was overexpressed in murine ATDC5 cells. In theseexperiments, it was clearly demonstrated that overexpression of SGK-1causes inhibition of cartilage synthesis. Both the amount of Alcian bluestained proteoglycan as well as aggrecan mRNA was significantly reduced.A kinase deficient SGK-1 form, however, had no negative effect on theseparameters. Regarding the effect of SGK-1 in OA diseased articularcartilage, several conclusions can be drawn from these experiments. Onthe one hand, SGK-1 expressing chondrocytes are no longer able tosynthesize sufficient extracellular matrix such as proteoglycans, whichare essential for the function of the tissue. On the other hand, thecartilage cells are inhibited to compensate for, or repair, degradationprocesses by increasing the expression of genes such as aggrecan.Therefore a function of SGK-1 as a potential cause and central factor ofOA pathology is confirmed. SGK-1 thus represents a highly relevanttarget molecule for the development of novel drugs for the treatment ofdegenerative cartilage changes, especially osteoarthritis.

In view of the relevance of SGK-1 for various physiological processesoutlined above, inhibitors of SGK-1 such as the compounds of the presentinvention can be used in the treatment, including therapy andprophylaxis, of various disease states in which SGK-1 activity plays arole or which are associated with an inappropriate SGK-1 activity, or inwhich an inhibition, regulation or modulation of signal transduction bySGK-1 is desired by the physician, for example degenerative jointdisorders and degenerative cartilage changes including osteoarthritis,osteoarthrosis, rheumatoid arthritis, spondylosis, chondrolysisfollowing joint trauma and prolonged joint immobilization after meniscusor patella injuries or ligament tears, connective tissue disorders suchas collagenoses, periodontal disorders, wound-healing disturbances,diabetes including diabetes mellitus, diabetic nephropathy, diabeticneuropathy, diabetic angiopathy and microangiopathy, obesity, metabolicsyndrome (dyslipidaemia), systemic and pulmonary hypertension, cerebralinfarctions, cardiovascular diseases including cardiac fibrosis aftermyocardial infarction, cardiac hypertrophy and heart failure,arteriosclerosis, renal diseases including glomerulosclerosis,nephrosclerosis, nephritis, nephropathy and electrolyte excretiondisorder, and any type of fibrosis and inflammatory processes includingliver cirrhosis, lung fibrosis, fibrosing pancreatitis, rheumatism,arthritis, gout, Crohn's disease, chronic bronchitis, radiationfibrosis, sclerodermatitis, cystic fibrosis, scar formation andAlzheimer's disease. Inhibitors of SGK-1 such as the compounds of thepresent invention can also be used in the treatment of pain includingacute pain like pain following injuries, post-operative pain, pain inassociation with an acute attack of gout and acute pain followingjaw-bone surgery interventions, and chronic pain like pain associatedwith chronic musculoskeletal diseases, back pain, pain associated withosteoarthritis or rheumatoid arthritis, pain associated withinflammation, amputation pain, pain associated with multiple sclerosis,pain associated with neuritis, pain associated with carcinomas andsarcomas, pain associated with AIDS, pain associated with chemotherapy,trigeminus neuralgia, headache, migraine cephalalgia, neuropathic pains,post-herpes zoster neuralgia. Inhibitors of SGK-1 such as the compoundsof the present invention can also be used in tumor therapy forinhibiting the growth of tumor cells and tumor metastases. Inhibitors ofSGK-1 such as the compounds of the present invention can also be usedfor the treatment of chronic disorders of the locomotor system such asinflammatory, immunologically or metabolically related acute and chronicarthritides, arthropathies, myalgias and disturbances of bonemetabolism. Further, inhibitors of SGK-1 such as the compounds of thepresent invention can be used in the treatment of peptic ulcers,especially in forms that are triggered by stress, in the treatment oftinnitus, in the treatment of bacterial infections and in anti-infectivetherapy, for increasing the learning ability and attention, forcounteracting cellular aging and stress and thus increasing lifeexpectancy and fitness in the elderly, in states of neuronalexcitability including epilepsy, in the treatment of glaucoma orcataracts, and in the treatment of coagulopathies includingdysfibrinogenaemia, hypoproconvertinaemia, haemophilia B, Stuart-Prowerdefect, prothrombin complex deficiency, consumption coagulopathy,fibrinolysis, immunokoagulopathy or complex coagulopathies.

Further details about the physiological role of SGK can be found, forexample, in the mentioned literature articles, the particulars of whichare as follows.

-   Akutsu, N., Lin. R., Bastien. Y., Bestawros, A., Enepekides, D. J.,    Black, M. J., and White, J. H. (2001). Regulation of gene Expression    by 1alpha,25-dihydroxyvitamin D3 and Its analog EB1089 under    growth-inhibitory conditions in squamous Carcinoma Cells. Mol    Endocrinol, 15, 1127-1139.-   Alliston, T. N., Maiyar, A. C., Buse, P., Firestone, G. L., and    Richards, J. S. (1997). Follicle stimulating hormone-regulated    expression of serum/glucocorticoid-inducible kinase in rat ovarian    granulosa cells: a functional role for the Sp1 family in Promoter    activity. Mol Endocrinol, 11, 1934-1949.-   Alliston, T. N., Gonzalez-Robayna, J. J., Buse, P., Firestone, G.    L., and Richards, J. S. (2000). Expression and localization of    serum/glucocorticoid-induced kinase in the rat ovary: relation to    follicular growth and differentiation. Endocrinology, 141, 385-395.-   Alvarez, d. I. R., Zhang, P., Naray-Fejes-Toth, A., Fejes-Toth, G.,    and Canessa, C. M. (1999). The serum and glucocorticoid kinase sgk    increases the abundance of epithelial sodium Channels in the plasma    membrane of Xenopus oocytes. J Biol Chem, 274, 37834-37839.-   Bartnik, E., Aigner, T., Dietz, U., and Brimmer, A., (2006). The use    of a Serum/Glucocorticoid-regulated Kinase. WO 06/061130.-   BelAiba, R. S., Djordjevic, T., Bonello, S., Artunc, F., Lang, F.,    Hess, J., and Gorlach, A. (2006). The serum- and    glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary    vascular remodeling: role in redox-sensitive regulation of tissue    factor by thrombin. Circ Res, 98, 828-836.-   Klingel, K., Warntges, S., Bock, J., Wagner, C. A., Sauter, M.,    Waldegger, S., Kandolf, R., and Lang, F. (2000). Expression of cell    volume-regulated kinase h-sgk in pancreatic tissue. Am J Physiol    Gastrointest Liver Physiol, 279, G998-G1002.-   Bhargava, A., Fullerton, M. J., Myles, K., Purdy, T. M., Funder, J.    W., Pearce, D., and Cole, T. J. (2001). The serum and    glucocorticoid-induced kinase is a physiological mediator of    aldosterone action. Endocrinology, 142, 1587-1594.-   Biondi, R. M., Kieloch, A., Currie, R. A., Deak, M., and    Alessi, D. R. (2001). The PIF-binding pocket in PDK1 is essential    for activation of S6K and SGK, but not PKB. EMBO J, 20, 4380-4390.-   Boehmer, C., Okur, F., Setiawan, I., Broer, S., and Lang, F.    (2003a). Properties and regulation of glutamine transporter SN1 by    protein kinases SGK and PKB. Biochem Biophys Res Commun, 306,    156-162.-   Boehmer, C., Wilhelm, V., Palmada, M., Wallisch, S., Henke, G.,    Brinkmeier, H., Cohen, P., Pieske, B., and Lang, F. (2003b). Serum    and glucocorticoid inducible kinases in the regulation of the    cardiac sodium Channel SCN5A. Cardiovasc Res, 57, 1079-1084.-   Boehmer, C, Wagner, C. A, Beck, S., Moschen, I., Melzig, J., Werner,    A., Lin, J. T., Lang, F., and Wehner, F. (2000). The    shrinkage-activated Na(+) conductance of rat hepatocytes and its    possible correlation to rENaC. Cell Physiol Biochem, 10, 187-194.-   Brennan, F. E. and Fuller, P. J. (2000). Rapid upregulation of serum    and glucocorticoidregulated kinase (sgk) gene expression by    corticosteroids in vivo. Mol Cell Endocrinol, 166, 129-136.-   Cooper, M. S., Bujalska, I., Rabbitt, E., Walker, E. A, Bland, R.,    Sheppard, M. C, Hewison, M., and Stewart, P. M. (2001). Modulation    of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory    cytokines in osteoblasts: an autocrine switch from glucocorticoid    inactivation to activation. J Bone Miner Res, 16, 1037-1044.-   Davies, S. P., Reddy, H., Caivano, M., and Cohen, P. (2000).    Specificity and mechanism of action of some commonly used protein    kinase inhibitors. Biochem J, 351, 95-105.-   Debonneville, C, Flores, S. Y., Kamynina, E., Plant, P. J., Tauxe,    C, Thomas, M. A., Munster, C., Chraibi, A., Pratt, J. H.,    Horisberger, J. D., Pearce, D., Loffing, J., and Staub, O. (2001).    Phosphorylation of Nedd-4-2 by Sgk1 regulates epithelial Na(+)    Channel cell surface expression. EMBO J, 20, 7052-7059.-   Faletti, C. J., Perrotti, N., Taylor, S. L, and Blazer-Yost, B. L.    (2002). sgk: an essential convergence point for peptide and Steroid    hormone regulation of ENaCmediated Na+ transport. Am J Physiol Cell    Physiol, 282, C494-0500.-   Feng, Y., Wang, Q., Wang, Y., Yard, B., Lang, F. (2005).    SGK1-mediated fibronectin formation in diabetic nephropathy. Cell    Physiol Biochem, 16, 237-244.-   Fillon, S., Klingel, K., Warntges, S., Sauter, M., Gabrysch, S.,    Pestel, S., Tanneur, V., Waldegger, S., Zipfel, A., Viebahn, R.,    Haussinger, D., Broer, S., Kandolf, R., and Lang, F. (2002).    Expression of the serine/threonine kinase hSGK1 in chronic viral    hepatitis. Cell Physiol Biochem, 12, 47-54.-   Firestone, G. L., Giampaolo, J. R., and O'Keeffe, B. A. (2003).    Stimulus-dependent regulation of serum and glucocorticoid inducible    protein kinase (SGK) transcription, subcellular localization and    enzymatic activity. Cell Physiol Biochem, 13, 1-12.-   Friedrich, B., Feng, Y., Cohen, P., Risler, T., Vandewalle, A.,    Broer, S., Wang, J., Pearce, D., Lang, F. (2003). The    serine/threonine kinases SGK2 and SGK3 are potent stimulators of the    epithelial Na(+) Channel alpha, beta, gamma-EnaC. Pflugers Arch,    445, 693-696.-   Funder, J. (2001). Mineralocorticoids and cardiac fibrosis: the    decade in review. Clin Exp Pharmacol Physiol, 28, 1002-1006.-   Gamper, N., Fillon, S., Huber, S. M., Feng, Y., Kobayashi, T.,    Cohen, P., and Lang, F. (2002). IGF-1 up-regulates K+ Channels via    PI3-kinase, PDK1 and SGK1. Pflugers Arch, 443, 625-634.-   Gonzalez-Robayna, I. J., Alliston, T. N., Buse, P., Firestone, G.    L., and Richards, J. S. (1999). Functional and subcellular changes    in the A-kinase-signaling pathway: relation to aromatase and Sgk    expression during the transition of granulosa cells to luteal cells.    Mol Endocrinol, 13, 1318-1337.-   Gonzalez-Robayna, I. J., Falender, A. E., Ochsner, S., Firestone, G.    L., and Richards, J. S. (2000). Follicle-Stimulating hormone (FSH)    stimulates phosphorylation and activation of protein kinase B    (PKB/Akt) and serum and glucocorticoid-Induced kinase (Sgk):    evidence for A kinase-independent signaling by FSH in granulosa    cells. Mol Endocrinol, 14, 1283-1300.-   Hayashi, M., Tapping, R. I., Chao, T. H., Lo, J. F., King, C. C.,    Yang, Y., Lee, J. D. (2001). BMK1 mediates growth factor-induced    cell proliferation through direct cellular activation of serum and    glucocorticoid-inducible kinase. J Biol Chem 276, 8631-8634.-   Henke, G., Maier, G., Wallisch, S., Boehmer, C., Lang, F. (2004).    Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin    ligase Nedd-4-2 and the serum and glucocorticoid inducible kinase    SGK1. J Cell Physiol, 199, 194-199.-   Imaizumi, K., Tsuda, M., Wanaka, A., Tohyama, M., and Takagi, T.    (1994). Differential expression of sgk mRNA, a member of the Ser/Thr    protein kinase gene family, in rat brain after CNS injury. Brain Res    Mol Brain Res, 26, 189-196.-   Kobayashi, T. and Cohen, P. (1999). Activation of serumand    glucocorticoid-regulated protein kinase by agonists that activate    phosphatidylinositide 3-kinase is mediated by    3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2.    Biochem J, 339(Pt2), 319-328.-   Kobayashi, T., Deak, M., Morrice, N., and Cohen, P. (1999).    Characterization of the structure and regulation of two novel    isoforms of serumand glucocorticoidinduced protein kinase. Biochem    J, 344(Pt1), 189-197.-   Kumar, J. M., Brooks, D. P., Olson, B. A., and Laping, N. J. (1999).    Sgk, a putative serine/threonine kinase, is differentially expressed    in the kidney of diabetic mice and humans. J Am Soc Nephrol, 10,    2488-2494.-   Lang, F., Henke, G., Embark, H. M., Waldegger, S., Palmada, M.,    Böhmer, C., Vallon, V. (2003). Regulation of channels by the serum    and glucocorticoid-inducible kinase-implications for transport,    excitability and cell proliferation. Cell Physiol Biochem, 13,    41-50.-   Lang, F., Klingel, K., Wagner, C. A., Stegen, C., Warttges, S.,    Friedrich, B., Lanzendorfer, M., Melzig, J., Moschen, I., Steuer,    S., Waldegger, S., Sauter, M., Paulmichl, M., Gerke, V., Risler, T.,    Gamba, G., Capasso, G., Kandolf, R., Hebert, S. C., Massry, S. G.,    and Broer, S. (2000). Deranged transcriptional regulation of    cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc Natl    Acad Sci U.S.A., 97, 8157-8162.-   Lee, E., Lein, E. S., Firestone, G. L. (2001). Tissue-specific    expression of the transcriptionally regulated serum and    glucocorticoid-inducible preotein kinase (sgk) during embryogenesis.    Mech Dev, 103, 177-181.-   Liu, D., Yang, X., and Songyang, Z. (2000). Identification of CISK,    a new member of the SGK kinase family that promotes IL-3-dependent    survival. Curr Biol, 10, 1233-1236.-   Loffing, J., Flores, S. Y., Staub, O. (2006). Sgk kinases and their    role in epithelial transport. Annu Rev Physiol, 68, 461-490.-   Loffing, J., Zecevic, M., Feraille, E., Kaissling, B., Asher, C,    Rossier, B. C., Firestone, G. L., Pearce, D., and Verrey, F. (2001).    Aldosterone induces rapid apical translocation of ENaC in early    portion of renal collecting System: possible role of SGK. Am J    Physiol Renal Physiol, 280, F675-F682-   McCormick, J. A., Bhalla, V., Pao, A. C., Pearce, D. (2005). SGK1: a    rapid aldosterone-induced regulator of renal sodium reabsorption.    Physiology (Bethesda), 20, 134-9.-   Mizuno, H. and Nishida, E. (2001). The ERK MAP kinase pathway    mediates induction of SGK (serumand glucocorticoid-inducible kinase)    by growth factors. Genes Cells, 6, 261-268.-   Park, J., Leong, M. L, Buse, P., Maiyar, A. C., Firestone, G. L, and    Hemmings, B. A. (1999). Serum and glucocorticoid-inducible kinase    (SGK) is a target of the PI 3-kinasestimulated signaling pathway.    EMBO J, 18, 3024-3033.-   Perrotti, N., He, R. A., Phillips, S. A., Haft, C. R., and    Taylor, S. I. (2001). Activation of serumand glucocorticoid-induced    protein kinase (Sgk) by cyclic AMP and insulin. J Biol Chem, 276,    9406-9412.-   Richards, J. S., Fitzpatrick, S. L., Clemens, J. W., Morris, J. K.,    Alliston, T., and Sirois, J. (1995). Ovarian cell differentiation: a    cascade of multiple hormones, cellular Signals, and regulated genes.    Recent Prag Horm Res, 50, 223-254.-   Rozansky, D. J., Wang, J., Doan, N., Purdy, T., Faulk, T., Bhargava,    A., Dawson, K., and Pearce, D. (2002). Hypotonie induction of SGK1    and Na+ transport in A6 cells. Am J Physiol Renal Physiol, 283,    F105-F113.-   Shenolikar, S. and Weinman, E. J. (2001). NHERF: targeting and    trafficking membrane proteins. Am J Physiol Renal Physiol, 280,    F389-F395.-   Shigaev, A., Asher, C., Latter, H., Garty, H., and Reuveny, E.    (2000). Regulation of sgk by aldosterone and its effects on the    epithelial Na(+) Channel. Am J Physiol Renal Physiol, 278,    F613-F619.-   Snyder, P. M., Olson, D. R., and Thomas, B. C. (2002). Serum and    glucocorticoidregulated kinase modulates Nedd-4-2-mediated    inhibition of the epithelial Na+ Channel. J Biol Chem, 277, 5-8.-   Staub, O., Gautschi, I., Ishikawa, T., Breitschopf, K., Ciechanover,    A., Schild, L., and Rotin, D. (1997). Regulation of stability and    function of the epithelial Na+ Channel (ENaC) by ubiquitination.    EMBO J, 16, 6325-6336.-   Vallon, V., Wulff, P., Huang, D. Y., Loffing, J., Voelkl, H., Kuhl,    D., Lang, F. (2005). Role of Sgk1 in salt and potassium homeostasis.    Am J Physiol Regul Integr Comp Physiol, 288, R4-R10.-   Vallon, V., and Lang, F. (2005). New insights into the role of    serum- and glucocorticoid-inducible kinase SGK1 in the regulation of    renal function and blood pressure. Curr Opin Nephrol Hypertens, 14,    59-66.-   Wagner, C. A., Broer, A., Albers, A., Gamper, N., Lang, F., and    Broer, S. (2000). The heterodimeric amino acid transporter    4F2hc/LAT1 is associated in Xenopus oocytes with a non-selective    cation Channel that is regulated by the serine/threonine kinase    sgk-1. J Physiol, 526(Pt1), 35-46.-   Wagner, C. A., Ott, M., Klingel, K., Beck, S., Melzig, J.,    Friedrich, B., Wild, K. N., Broer, S., Moschen, I., Albers, A.,    Waldegger, S., Tummler, B., Egan, M. E., Geibel, J. P., Kandolf, R.,    and Lang, F. (2001). Effects of the serine/threonine kinase SGK1 on    the epithelial Na(+) Channel (ENaC) and CFTR: implications for    cystic fibrosis. Cell Physiol Biochem, 11, 209-218.-   Waldegger, S., Barth, P., Raber, G., and Lang, F. (1997). Cloning    and characterization of a putative human serine/threonine protein    kinase transcriptionally modified during anisotonic and isotonic    alterations of cell volume. Proc Natl Acad Sci U.S.A., 94,    4440-4445.-   Waldegger, S., Gabrysch, S., Barth., P., Fillon, S., and Lang, F.    (2000). h-sgk serinethreonine protein kinas[theta] as    transcriptional target of p38/MAP kinase pathway in HepG2 human    hepatoma cells. Cell Physiol Biochem, 10, 203-208.-   Waldegger, S., Klingel, K., Barth, P., Sauter, M., Rfer. M. L.,    Kandolf, R., and Lang, F. (1999). h-sgk serine-threonine protein    kinase gene as transcriptional target of transforming growth factor    beta in human intestine. Gastroenterology, 116, 1081-1088.-   Wang, J., Barbry, P., Maiyar, A. C., Rozansky, D. J., Bhargava, A.,    Leong, M., Firestone, G. L., and Pearce, D. (2001). SGK integrates    insulin and mineralocorticoid regulation of epithelial sodium    transport. Am J Physiol Renal Physiol, 280, F303-F313.-   Warntges, S., Friedrich, B., Henke, G., Duranton, C, Lang, P. A.,    Waldegger, S., Meyermann, R., Kühl, D., Speckmann, E. J.,    Obermuller, N., Witzgall, R., Mack, A. F., Wagner, H. J., Wagner,    A., Broer, S., and Lang, F. (2002a). Cerebral localization and    regulation of the cell volume-sensitive serumand    glucocorticoid-dependent kinase SGK1. Pflugers Arch, 443, 617-624.-   Warntges, S., Klingel, K., Weigert, C, Fillon, S., Buck, M.,    Schleicher, E., Rodemann, H. P., Knabbe, C, Kandolf, R., and    Lang, F. (2002b). Excessive transcription of the human serum and    glucocorticoid dependent kinase hSGK1 in lung fibrosis. Cell Physiol    Biochem, 12, 135-142.-   Webster, M. K., Goya, L., and Firestone, G. L. (1993a).    Immediate-early transcriptional regulation and rapid mRNA turnover    of a putative serine/threonine protein kinase. J Biol Chem, 268,    11482-11485.-   Webster, M. K., Goya, L, Ge, Y., Maiyar, A. C, and Firestone, G. L.    (1993b). Characterization of sgk, a novel member of the    serine/threonine protein kinase gene family which is    transcriptionally induced by glucocorticoids and serum. Mol Cell    Biol, 13, 2031-2040.-   Yun, C. C. (2003). Concerted roles of SGK1 and the Na+/H+ exchanger    regulatory factor 2 (NHERF2) in regulation of NHE3. Cell Physiol    Biochem, 13, 29-40. Yun, C. C., Chen. Y., and Lang, F. (2002).    Glucocorticoid activation of Na(+)/H(+) exchanger isoform 3    revisited. The roles of SGK1 and NHERF2. J Biol Chem, 277,    7676-7683.

The identification of small compounds that specifically inhibit,regulate or modulate signal transduction by SGK, is therefore desirableand an object of the present invention. But besides being effective SGKinhibitors, it is desirable that such inhibitors also have furtheradvantageous properties, for example high bioavailability, stability inplasma and liver, and selectivity versus other kinases or receptorswhose inhibition or activation is not intended. Thus, it is an object ofthe present invention to provide SGK inhibitors which effectivelyinhibit an aberrant activity of SGK in a pathological context and whichhave further advantageous properties, for example high bioavailability,stability in plasma and liver, and selectivity versus other kinases andreceptors which are not intended to be influenced in an agonistic orantagonistic manner. This object is achieved by providing the novelcompounds of the formula I which exhibit excellent SGK-1 inhibitoryactivity and are favorable agents with high bioavailability andstability in plasma and liver.

Thus, a subject of the present invention are the compounds of theformula I, in any of their stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, and the pharmaceutically acceptablesalts thereof,

wherein

-   Ar is selected from the series consisting of phenyl and a 5-membered    or 6-membered monocyclic aromatic heterocycle comprising 1, 2 or 3    identical or different ring heteroatoms selected from the series    consisting of nitrogen, oxygen and sulfur and bonded via a ring    carbon atom, which are all unsubstituted or substituted by one or    more identical or different substituents R10;-   n is selected from the series consisting of 0, 1 and 2;-   R1 is selected from the series consisting of hydrogen, —N(R11)-R12,    —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14,    —C(O)—N(R16)-R17, —CN, (C₁-C₄)-alkyl and —(C₁-C₄)-alkyl-O—R18;-   R2 is selected from the series consisting of halogen, (C₁-C₄)-alkyl,    —O—(C₁-C₄)-alkyl and —CN;-   R10 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl,    —O—(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl-,    —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO₂,    —C(O)—N(R23)-R24 and —CN,-   and two groups R10 bonded to adjacent ring carbon atoms in Ar,    together with the carbon atoms carrying them, can form a 5-membered    to 8-membered unsaturated ring which comprises 0, 1 or 2 identical    or different ring heteroatoms selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of halogen, (C₁-C₄)-alkyl,    —O—(C₁-C₄)-alkyl and —CN;-   R11 and R12 are independently of one another selected from the    series consisting of hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and    —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl,-   or R11 and R12, together with the nitrogen atom carrying them, form    a monocyclic, 4-membered to 7-membered, saturated heterocycle which,    in addition to the nitrogen atom carrying R11 and R12, comprises 0    or 1 further ring heteroatom selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R13 is selected from the series consisting of hydrogen,    (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl;-   R14 and R15 are independently of one another selected from the    series consisting of (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,    —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl,    Het and —(C₁-C₄)-alkyl-Het, wherein phenyl and Het all are    unsubstituted or substituted by one or more identical or different    substituents R30;-   R16 is selected from the series consisting of hydrogen,    (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl;-   R17 is selected from the series consisting of hydrogen,    (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,    —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl,    Het and —(C₁-C₄)-alkyl-Het, wherein phenyl and Het all are    unsubstituted or substituted by one or more identical or different    substituents R30,-   or R16 and R17, together with the nitrogen atom carrying them, form    a monocyclic, 4-membered to 7-membered, saturated heterocycle which,    in addition to the nitrogen atom carrying R16 and R17, comprises 0    or 1 further ring heteroatom selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R18 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R19 is selected from the series consisting of hydrogen,    (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl;-   R20 is selected from the series consisting of hydrogen,    (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,    —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl,    Het and —(C₁-C₄)-alkyl-Het, wherein phenyl and Het all are    unsubstituted or substituted by one or more identical or different    substituents R30,-   or R19 and R20, together with the nitrogen atom carrying them, form    a monocyclic, 4-membered to 7-membered, saturated heterocycle which,    in addition to the nitrogen atom carrying R19 and R20, comprises 0    or 1 further ring heteroatom selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R21 is selected from the series consisting of hydrogen,    (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl;-   R22 is selected from the series consisting of (C₁-C₄)-alkyl,    (C₃-C₇)-cycloalkyl and —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl;-   R23 and R24 are independently of one another selected from the    series consisting of hydrogen and (C₁-C₄)-alkyl;-   R30 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl and —CN;-   Het is a monocyclic, 4-membered to 7-membered, saturated, partially    unsaturated or aromatic heterocycle which comprises 1 or 2 identical    or different ring heteroatoms selected from the series consisting of    nitrogen, oxygen and sulfur, and which is bonded via a ring carbon    atom;-   wherein all cycloalkyl groups can be substituted by one or more    identical substituents selected from the series consisting of    fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents.

If structural elements such as groups, substituents or numbers, forexample, can occur several times in the compounds of the formula I, theyare all independent of each other and can in each case have any of theindicated meanings, and they can in each case be identical to ordifferent from any other such element. In a dialkylamino group, forexample, the alkyl groups can be identical or different.

Alkyl groups, i.e. saturated hydrocarbon residues, can be linear(straight-chain) or branched. This also applies if these groups aresubstituted or are part of another group, for example an —O-alkyl group(alkyloxy group, alkoxy group) or an HO-substituted alkyl group(-alkyl-OH, hydroxyalkyl group). Depending on the respective definition,the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, 6, 7or 8, 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2,or 1. Examples of alkyl are methyl, ethyl, propyl including n-propyl andisopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl,pentyl including n-pentyl, 1-methylbutyl, isopentyl, neopentyl andtert-pentyl, hexyl including n-hexyl, 2,2-dimethylhexyl,3,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and isohexyl, heptylincluding n-heptyl, and octyl including n-octyl. Examples of —O-alkylgroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy.

A substituted alkyl group can be substituted in any positions, providedthat the respective compound is sufficiently stable and is suitable as apharmaceutical active compound. The prerequisite that a specific groupand a compound of the formula I are sufficiently stable and suitable asa pharmaceutical active compound, applies in general with respect to thedefinitions of all groups in the compounds of the formula I. An alkylgroup which, independently of any other substituents, can be substitutedby one or more fluorine substituents, can be unsubstituted by fluorinesubstituents, i.e. not carry fluorine substituents, or substituted, forexample by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorine substituents, orby 1, 2, 3, 4 or 5 fluorine substituents, or by 1, 2 or 3 fluorinesubstituents, which can be located in any positions. For example, in afluoro-substituted alkyl group one or more methyl groups can carry threefluorine substituents each and be present as trifluoromethyl groups,and/or one or more methylene groups (CH₂) can carry two fluorinesubstituents each and be present as difluoromethylene groups. Theexplanations with respect to the substitution of a group by fluorinealso apply if the group additionally carries other substituents and/oris part of another group, for example of an —O-alkyl group. Examples offluoro-substituted alkyl groups are —CF₃ (trifluoromethyl), —CHF₂,—CH₂F, —CHF—CF₃, —CHF—CHF₂, —CHF—CH₂F, —CH₂—CF₃, —CH₂—CHF₂, —CH₂—CH₂F,—CF₂—CF₃, —CF₂—CHF₂, —CF₂—CH₂F, —CH₂—CHF—CF₃, —CH₂—CHF—CHF₂,—CH₂—CHF—CH₂F, —CH₂—CH₂—CF₃, —CH₂—CH₂—CHF₂, —CH₂—CH₂—CH₂F, —CH₂—CF₂—CF₃,—CH₂—CF₂—CHF₂, —CH₂—CF₂—CH₂F, —CHF—CHF—CF₃, —CHF—CHF—CHF₂,—CHF—CHF—CH₂F, —CHF—CH₂—CF₃, —CHF—CH₂—CHF₂, —CHF—CH₂—CH₂F, —CHF—CF₂—CF₃,—CHF—CF₂—CHF₂, —CHF—CF₂—CH₂F, —CF₂—CHF—CF₃, —CF₂—CHF—CHF₂,—CF₂—CHF—CH₂F, —CF₂—CH₂—CF₃, —CF₂—CH₂—CHF₂, —CF₂—CH₂—CH₂F, —CF₂—CF₂—CF₃,—CF₂—CF₂—CHF₂, or —CF₂—CF₂—CH₂F. Examples of fluoro-substituted —O-alkylgroups are trifluoromethoxy (—OCF₃), 2,2,2-trifluoroethoxy,pentafluoroethoxy and 3,3,3-trifluoropropoxy. With respect to all groupsor substituents in the compounds of the formula I which can be an alkylgroup which can generally contain one or more fluorine substituents, asan example of groups or substituents containing fluorine-substitutedalkyl which may be included in the definition of the group orsubstituent, the group CF₃ (trifluoromethyl), or a respective group suchas CF₃—O—, may be mentioned.

The above explanations with respect to alkyl groups applycorrespondingly to alkyl groups which in the definition of a group inthe compounds of the formula I are bonded to two adjacent groups, orlinked to two groups, and may be regarded as divalent alkyl groups(alkanediyl groups), like in the case of the alkyl part of a substitutedalkyl group. Thus, such groups can also be linear or branched, the bondsto the adjacent groups can be located in any positions and can startfrom the same carbon atom or from different carbon atoms, and they canbe unsubstituted or substituted by fluorine substituents independentlyof any other substituents. Examples of such divalent alkyl groups are—CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—, —CH₂—C(CH₃)₂—. Examples offluoro-substituted alkanediyl groups, which can contain 1, 2, 3, 4, 5 or6 fluorine substituents, or 1, 2, 3 or 4 fluorine substituents, or 1 or2 fluorine substituents, for example, are —CF₂—, —CHF—, —CHF—CHF₂—,—CHF—CHF—, —CH₂—CF₂—, —CH₂—CHF—, —CF₂—CF₂—, —CF₂—CHF—, —CH₂—CHF—CF₂—,—CH₂—CHF—CHF—, —CH₂—CH₂—CF₂—, —CH₂—CH2-CHF, —CH₂—CF₂—CF₂—,—CH₂—CF₂—CHF—, —CHF—CHF—CF₂—, —CHF—CHF—CHF—, —CHF—CH₂—CF₂—,—CHF—CH₂—CHF—, —CHF—CF₂—CF₂—, —CHF—CF₂—CHF—, —CF₂—CHF—CF₂—,—CF₂—CHF—CHF—, —CF₂—CH₂—CF₂—, —CF₂—CH₂—CHF—, —CF₂—CF₂—CF₂—, or—CF₂—CF₂—CHF.

The number of ring carbon atoms in a (C₃-C₇)-cycloalkyl group can be 3,4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl which, independentlyof any other substituents, can be substituted by one or more(C₁-C₄)-alkyl substituents, can be unsubstituted by alkyl substituents,i.e. not carry alkyl substituents, or substituted, for example by 1, 2,3 or 4 identical or different (C₁-C₄)-alkyl substituents, for example bymethyl groups, which substituents can be located in any positions.Examples of such alkyl-substituted cycloalkyl groups are1-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-methylcyclopentyl,2,3-dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl,4-isopropylcyclohexyl, 4-tert-butylcyclohexyl,3,3,5,5-tetramethylcyclohexyl. Cycloalkyl groups which, independently ofany other substituents, can be substituted by one or more fluorinesubstituents, can be unsubstituted by fluorine substituents, i.e. notcarry fluorine substituents, or substituted, for example by 1, 2, 3, 4,5, 6, 7, 8, 9, 10 or 11 fluorine substituents, or by 1, 2, 3, 4, 5 or 6fluorine substituents, or by 1, 2 or 3 fluorine substituents. Thefluorine substituents can be located in any positions of the cycloalkylgroup and can also be located in an alkyl substituent. Examples offluoro-substituted cycloalkyl groups are 1-fluorocyclopropyl,2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl,4,4-difluorocyclohexyl, 3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkylgroups can also be substituted simultaneously by fluorine and alkyl.Examples of the group —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl arecyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-,cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-,2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-,1-cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-,2-cyclohexylethyl-, 1-cycloheptylethyl-, 2-cycloheptylethyl-. In oneembodiment of the invention, a —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl groupin any one or more occurrences of such a group, independently of anyother occurrences, is a —(C₁-C₂)-alkyl-(C₃-C₇)-cycloalkyl group, inanother embodiment a —CH₂—(C₃-C₇)-cycloalkyl group. In the group—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, and likewise in all other groups, theterminal hyphen denotes the free bond via which the group is bonded, andthus indicates via which subgroup a group composed of subgroups isbonded.

In substituted phenyl groups, including phenyl groups representing Ar,the substituents can be located in any positions. In monosubstitutedphenyl groups, the substituent can be located in position 2, in position3 or in position 4. In disubstituted phenyl groups, the substituents canbe located in positions 2 and 3, in positions 2 and 4, in positions 2and 5, in positions 2 and 6, in positions 3 and 4, or in positions 3 and5. In trisubstituted phenyl groups, the substituents can be located inpositions 2, 3 and 4, in positions 2, 3 and 5, in positions 2, 3 and 6,in positions 2, 4 and 5, in positions 2, 4 and 6, or in positions 3, 4and 5. If a phenyl group carries four substituents, some of which can befluorine atoms, for example, the substituents can be located inpositions 2, 3, 4 and 5, in positions 2, 3, 4 and 6, or in positions 2,3, 5 and 6. If a polysubstituted phenyl group or any otherpolysubstituted group carries different substituents, each substituentcan be located in any suitable position, and the present inventioncomprises all positional isomers. The number of substituents in asubstituted phenyl group can be 1, 2, 3, 4 or 5. In one embodiment ofthe invention, the number of substituents in a substituted phenyl group,like the number of substituents in any other substituted group which cancarry one or more substituents, for example the group Het, is 1, 2, 3 or4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, inanother embodiment 1, where the number of substituents in any occurrenceof such a substituted group is independent of the number of substituentsin other occurrences.

In heterocyclic groups, including the group Het, heterocyclesrepresenting Ar and other heterocyclic rings which can be present in thecompounds of the formula I, such as rings formed by two group togetherwith the atom or atoms carrying them, the hetero ring members can bepresent in any combination and located in any suitable ring positions,provided that the resulting group and the compound of the formula I aresuitable and sufficiently stable as a pharmaceutical active compound. Inone embodiment of the invention, two oxygen atoms in any heterocyclicring in the compounds of the formula I cannot be present in adjacentring positions. In another embodiment of the invention, two hetero ringmembers selected from the series consisting of oxygen atoms and sulfuratoms cannot be present in adjacent ring positions in any heterocyclicring in the compounds of the formula I. In another embodiment of theinvention, two hetero ring members selected from the series consistingof nitrogen atoms carrying an exocyclic group like a hydrogen atom or asubstituent, sulfur atoms and oxygen atoms cannot be present in adjacentring positions in any heterocyclic ring in the compounds of the formulaI. The choice of hetero ring members in an aromatic heterocyclic ring islimited by the prerequisite that the ring is aromatic, i.e. it comprisesa cyclic system of six delocalized pi electrons. Monocyclic aromaticheterocycles are 5-membered or 6-membered rings and, in the case of a5-membered ring, comprise one ring heteroatom selected from the seriesconsisting of oxygen, sulfur and nitrogen, wherein this ring nitrogencarries an exocyclic group like a hydrogen atom or a substituent, andoptionally one or more further ring nitrogen atoms, and, in the case ofa 6-membered ring, comprise one or more nitrogen atoms as ringheteroatoms, but no oxygen atoms and sulfur atoms as ring heteroatoms.Heterocyclic groups in the compounds of the formula I are bonded via aring carbon atom or a ring nitrogen atom, as specified in the definitionof the respective group, where a heterocyclic group can be bonded viaany suitable carbon atom or nitrogen atom, respectively, in the ring. Insubstituted heterocyclic groups, the substituents can be located in anypositions.

The number of ring heteroatoms which can be present in a heterocyclicgroup in the compounds of the formula I, the number of ring memberswhich can be present, and the degree of saturation, i.e. whether theheterocyclic group is saturated and does not contain a double bondwithin the ring, or whether it is partially unsaturated and contains oneor more, for example one or two, double bonds within the ring but is notaromatic, or whether it is aromatic and thus contains two double bondswithin the ring in the case of a 5-membered monocyclic aromaticheterocycle and three double bonds within the ring in the case of a6-membered monocyclic aromatic heterocycle, is specified in thedefinitions of the individual groups in the compounds of the formula I.As examples of heterocyclic ring systems, from which heterocyclic groupsin the compounds of the formula I including the bicyclic heterocyclicring system which can result in case two groups R10 bonded to adjacentring carbon atoms in Ar together with the carbon atoms carrying themform a ring, can be derived, and from any one or more of which any ofthe heterocyclic groups in the compounds of the formula I is selected inone embodiment of the invention, provided that the ring system iscomprised by the definition of the group, oxetane, thietane, azetidine,furan, tetrahydrofuran, thiophene, tetrahydrothiophene, pyrrole,pyrroline, pyrrolidine, 1,3-dioxole, 1,3-dioxolane, isoxazole([1,2]oxazole), isoxazoline, isoxazolidine, oxazole ([1,3]oxazole),oxazoline, oxazolidine, isothiazole ([1,2]thiazole), isothiazoline,isothiazolidine, thiazole ([1,3]thiazole), thiazoline, thiazolidine,pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline,imidazolidine, [1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxadiazole,[1,3,4]oxadiazole, 1,2,5-oxadiazole, [1,2,4]thiadiazole, pyran,tetrahydropyran, thiopyran, tetrahydrothiopyran,2,3-dihydro[1,4]dioxine, 1,4-dioxane, pyridine,1,2,5,6-tetrahydropyridine, piperidine, morpholine, thiomorpholine,piperazine, pyridazine, pyrimidine, pyrazine, [1,2,4]triazine, oxepane,thiepane, azepane, [1,3]diazepane, [1,4]diazepane, [1,4]oxazepane,[1,4]thiazepane, benzofuran, isobenzofuran, benzothiophene(benzo[b]thiophene), 1H-indole, 2,3-dihydro-1H-indole, 2H-isoindole,benzo[1,3]dioxole, benzoxazole, benzthiazole, 1H-benzimidazole, chroman,isochroman, thiochroman, benzo[1,4]dioxane,3,4-dihydro-2H-benzo[1,4]oxazine, 3,4-dihydro-2H-benzo[1,4]thiazine,quinoline, 5,6,7,8-tetrahydroquinoline, isoquinoline,5,6,7,8-tetrahydroisoquinoline, cinnoline, quinazoline, quinoxaline,phthalazine, [1,8]naphthyridine and3,4-dihydro-2H-benzo[b][1,4]dioxepine, which latter ring system may alsobe named as 3,4-dihydro-2H-1,5-benzodioxepine, may be mentioned, whichcan all be unsubstituted or substituted in any suitable positions asspecified in the definition of the respective group in the compounds ofthe formula I, wherein the given degree of unsaturation is by way ofexample only, and in the individual groups also ring systems with ahigher or lower degree of saturation, or hydrogenation, or ofunsaturation can be present as specified in the definition of the group.Ring sulfur atoms, in particular in saturated and partially unsaturatedheterocycles, can generally carry one or two oxo groups, i.e. doublybonded oxygen atoms, and in such heterocycles, besides a ring sulfuratom, also an S(O) group (S(═O)) and an S(O)₂ group (S(═O)₂) can bepresent as hetero ring member.

As mentioned, the heterocyclic groups can be bonded via any suitablering atom as specified in the definition of the respective group in thecompound of the formula I. For example, among others can an oxetane anda thietane ring be bonded via positions 2 and 3, an azetidine ring viapositions 1, 2 and 3, a furan ring, a tetrahydrofuran ring, a thiophenering and a tetrahydrothiophene via positions 2 and 3, a pyrrole ring anda pyrrolidine ring via positions 1, 2 and 3, an isoxazole ring and anisothiazole ring via positions 3, 4 and 5, a pyrazole ring via positions1, 3, 4 and 5, an oxazole ring and a thiazole ring via positions 2, 4and 5, an imidazole ring and an imidazolidine ring via positions 1, 2, 4and 5, a tetrahydropyran and a tetrahydrothiopyran ring via positions 2,3 and 4, a 1,4-dioxane ring via position 2, a pyridine ring viapositions 2, 3 and 4, a piperidine ring via positions 1, 2, 3 and 4, amorpholine ring and a thiomorpholine ring via positions 2, 3 and 4, apiperazine ring via positions 1 and 2, a pyrimidine ring via positions2, 4 and 5, a pyrazine ring via position 2, an azepane ring viapositions 1, 2, 3 and 4, a benzofuran ring and a benzothiophene ring viapositions 2, 3, 4, 5, 6 and 7, a 1H-indole ring and a2,3-dihydro-1H-indole ring via positions 1, 2, 3, 4, 5, 6 and 7, abenzo[1,3]dioxole ring via positions 4, 5, 6 and 7, a benzoxazole ringand a benzthiazole ring via positions 2, 4, 5, 6 and 7, a1H-benzimidazole ring via positions 1, 2, 4, 5, 6 and 7, abenzo[1,4]dioxane ring via positions 5, 6, 7 and 8, a quinoline ring viapositions 2, 3, 4, 5, 6, 7 and 8, a 5,6,7,8-tetrahydroquinoline viapositions 2, 3 and 4, an isoquinoline ring via positions 1, 3, 4, 5, 6,7 and 8, a 5,6,7,8-tetrahydroisoquinoline ring via positions 1, 3 and 4,for example, wherein the resulting residues of the heterocyclic groupscan all be unsubstituted or substituted in any suitable positions asspecified in the definition of the respective group in the compounds ofthe formula I.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment ofthe invention, halogen is in any of its occurrences fluorine, chlorineor bromine, in another embodiment fluorine or chlorine, in anotherembodiment fluorine, in another embodiment chlorine, where alloccurrences of halogen are independent of each other.

The present invention comprises all stereoisomeric forms of thecompounds of the formula I, for example all enantiomers anddiastereomers including cis/trans isomers. The invention likewisecomprises mixtures of two or more stereoisomeric forms, for examplemixtures of enantiomers and/or diastereomers including cis/transisomers, in all ratios. Asymmetric centers contained in the compounds ofthe formula I can all independently of each other have S configurationor R configuration. The invention relates to enantiomers, both thelevorotatory and the dextrorotatory antipode, in enantiomerically pureform and essentially enantiomerically pure form, and in the form oftheir racemate, i.e. a mixture of the two enantiomers in molar ratio of1:1, and in the form of mixtures of the two enantiomers in all ratios.The invention likewise relates to diastereomers in the form of pure andessentially pure diastereomers and in the form of mixtures of two ormore diastereomers in all ratios. The invention also comprises allcis/trans isomers of the compounds of the formula I in pure form andessentially pure form, and in the form of mixtures of the cis isomer andthe trans isomer in all ratios. Cis/trans isomerism can occur insubstituted rings. The preparation of individual stereoisomers, ifdesired, can be carried out by resolution of a mixture according tocustomary methods, for example, by chromatography or crystallization, orby use of stereochemically uniform starting compounds in the synthesis,or by stereoselective reactions. Optionally, before a separation ofstereoisomers a derivatization can be carried out. The separation of amixture of stereoisomers can be carried out at the stage of the compoundof the formula I or at the stage of an intermediate in the course of thesynthesis. For example, in the case of a compound of the formula Icontaining an asymmetric center the individual enantiomers can beprepared by preparing the racemate of the compound of the formula I andresolving it into the enantiomers by high pressure liquid chromatographyon a chiral phase according to standard procedures, or resolving theracemate of any intermediate in the course of its synthesis by suchchromatography or by crystallization of a salt thereof with an opticallyactive amine or acid and converting the enantiomers of the intermediateinto the enantiomeric forms of the final compound of the formula I, orby performing an enantioselective reaction in the course of thesynthesis. The invention also comprises all tautomeric forms of thecompounds of the formula I.

Besides the free compounds of the formula I, i.e. compounds in whichacidic and basic groups are not present in the form of a salt, thepresent invention comprises also the physiologically or toxicologicallyacceptable salts of the compounds of the formula I, especially theirpharmaceutically acceptable salts, which can be formed on one or moreacidic or basic groups in the compounds of the formula I, for example onbasic heterocyclic moieties. The compounds of the formula I may thus bedeprotonated on an acidic group by an inorganic or organic base and beused, for example, in the form of the alkali metal salts. Compounds ofthe formula I comprising at least one basic group may also be preparedand used in the form of their acid addition salts, for example in theform of pharmaceutically acceptable salts with inorganic acids andorganic acids, such as salts with hydrochloric acid and thus be presentin the form of the hydrochlorides, for example. Salts can in general beprepared from acidic and basic compounds of the formula I by reactionwith an acid or base in a solvent or diluent according to customaryprocedures. If the compounds of the formula I simultaneously contain anacidic and a basic group in the molecule, the invention also includesinternal salts (betaines, zwitterions) in addition to the salt formsmentioned. The present invention also comprises all salts of thecompounds of the formula I which, because of low physiologicaltolerability, are not directly suitable for use as a pharmaceutical, butare suitable as intermediates for chemical reactions or for thepreparation of physiologically acceptable salts, for example by means ofanion exchange or cation exchange.

In one embodiment of the invention, an aromatic heterocycle representingthe group Ar comprises 1 or 2 identical or different ring heteroatoms,in another embodiment 1 or 2 identical or different ring heteroatomswhich are selected from the series consisting of nitrogen and sulfur. Inanother embodiment, an aromatic heterocycle representing Ar is a5-membered heterocycle which comprises 1 or 2 identical or differentring heteroatoms which are selected from the series consisting ofnitrogen and sulfur, or it is a 6-membered heterocycle which comprises 1or 2 ring heteroatoms which are nitrogen atoms, in another embodiment itis a 5-membered heterocycle which comprises 1 or 2 identical ordifferent ring heteroatoms which are selected from the series consistingof nitrogen and sulfur. In another embodiment, an aromatic heterocyclerepresenting Ar is selected from the series consisting of thiophene,thiazole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine andpyrazine, in another embodiment from the series consisting of thiophene,thiazole, pyrazole, imidazole and pyridine, in another embodiment fromthe series consisting of thiophene, thiazole, pyrazole and imidazole, inanother embodiment from the series consisting of thiophene and pyrazole,in another embodiment it is thiophene, and in another embodiment it ispyrazole, which heterocycles are all unsubstituted or substituted by oneor more substituents R10. In one embodiment of the invention, Ar isphenyl which is unsubstituted or substituted by one or more identical ordifferent substituents R10, in another embodiment Ar is phenyl which issubstituted by one or more identical or different substituents R10, inanother embodiment Ar is a 5-membered or 6-membered aromatic heterocyclewhich is unsubstituted or substituted by one or more identical ordifferent substituents R10, and in another embodiment Ar is a 5-memberedor 6-membered aromatic heterocycle which is substituted by one or moreidentical or different substituents R10. In one embodiment of theinvention, the number of identical or different substituents R10 whichcan be present in the group Ar is 1, 2, 3 or 4, in another embodiment itis 1, 2 or 3, in another embodiment it is 1 or 2, in another embodimentit is 1, in another embodiment it is 2, 3 or 4, in another embodiment itis 2 or 3, in another embodiment it is 3, in another embodiment it is 2.In one embodiment, Ar is substituted by one or more identical ordifferent substituents R10.

In one embodiment of the invention, the number n is selected from theseries consisting of 0 and 1, in another embodiment from the seriesconsisting of 1 and 2, in another embodiment it is 1, in anotherembodiment it is 0.

In one embodiment of the invention, R1 is selected from the seriesconsisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14,—N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14, (C₁-C₄)-alkyl and—(C₁-C₄)-alkyl-O—R18, in another embodiment from the series consistingof hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15,—N(R13)-C(O)—NH—R14, —C(O)—N(R16)-R17, —CN and (C₁-C₄)-alkyl, in anotherembodiment from the series consisting of hydrogen, —N(R11)-R12,—N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14 and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen, —C(O)—N(R16)-R17, —CN, (C₁-C₄)-alkyl and —(C₁-C₄)-alkyl-O—R18,in another embodiment from the series consisting of hydrogen and(C₁-C₄)-alkyl, in another embodiment from the series consisting of—N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15 and—N(R13)-C(O)—NH—R14, in another embodiment from the series consisting of—N(R11)-R12 and —N(R13)-C(O)—R14, in another embodiment it is—N(R11)-R12, and in another embodiment R1 is selected from the seriesconsisting of —N(R11)-R12 and (C₁-C₄)-alkyl. In one embodiment, a(C₁-C₄)-alkyl group representing R1 is (C₁-C₂)-alkyl, in anotherembodiment it is methyl.

In one embodiment of the invention, R2 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl and —CN, in another embodiment fromthe series consisting of halogen and (C₁-C₄)-alkyl, in anotherembodiment from the series consisting of halogen and —CN, in anotherembodiment from the series consisting of halogen. In one embodiment, a(C₁-C₄)-alkyl group present in R2 is a methyl group. In one embodiment,halogen representing R2 is selected from the series consisting offluorine and chlorine, in another embodiment it is fluorine. Ring carbonatoms in the divalent phenyl group depicted in formula I which have afree binding site, i.e. are not bonded to adjacent groups in formula I,and which do not carry a group R2, carry hydrogen atoms, as doeslikewise the carbon atom in position 5 of the pyrazolo[3,4-b]pyrazinering system depicted in formula I. Thus, in case the number n is 0 andhence no group R2 is present, all four carbon atoms in the ringpositions of the divalent phenyl group depicted in formula I which informula I′ are designated as positions 2′, 3′, 5′ and 6′, carry hydrogenatoms. In case the number n is 1 and hence one group R2 is present, oneof the four carbon atoms in the ring positions of the divalent phenylgroup depicted in formula I which in formula I′ are designated as 2′,3′, 5′ and 6′, carries the group R2 and the other three said carbonatoms carry hydrogen atoms. In case the number n is 2 and hence twogroups R2 are present, two of the four carbon atoms in the ringpositions of the divalent phenyl group depicted in formula I which informula I′ are designated as positions 2′, 3′, 5′ and 6′, carry thegroups R2 and the other two said carbon atoms carry hydrogen atoms.

Groups R2 can be present in any positions of the divalent phenyl groupdepicted in formula I which have a free binding site. If one group R2 ispresent, in one embodiment of the invention the group R2 is present inthe position which is formula I′ is designated as position 2′, which isequivalent to position 6′, and in another embodiment it is present inthe position which in formula I′ is designated as position 3′, which isequivalent to position 5′. If two groups R2 are present, in oneembodiment of the invention the groups R2 are present in the positionswhich in formula I′ are designated as positions 2′ and 3′, in anotherembodiment in the positions which in formula I′ are designated aspositions 2′ and 5′, in another embodiment in the positions which informula I′ are designated as positions 2′ and 6′, in another embodimentin the positions which in formula I′ are designated as positions 3′ and5′.

If two groups R10 bonded to adjacent ring carbon atoms in Ar togetherwith the ring carbon atoms carrying them form a 5-membered to 8-memberedring, this ring is at least mono-unsaturated, i.e., the resulting ringcontains at least one double bond within the ring, which double bond ispresent between the said two adjacent ring carbon in the aromatic ringAr which are common to the ring Ar and the ring formed by the two groupsR10, and because of the rules of nomenclature for fused rings isregarded as a double bond present in both rings. The ring formed by twogroups R10 together with the carbon atoms carrying them can contain 1, 2or 3 double bonds within the ring. In one embodiment, the formed ringcontains 1 or 2 double bonds, in another embodiment 1 double bond withinthe ring. In the case of a 6-membered carbocyclic or heterocyclic ringor a 5-membered heterocyclic ring the formed ring can be aromatic and,together with the aromatic ring Ar, form a bicyclic aromatic ringsystem, for example a naphthalene ring system, a quinoline ring system,an isoquinoline ring system or a benzothiophene ring system. The casethat two groups R10 bonded to adjacent ring carbon atoms in Ar togetherwith the carbon atoms carrying them form a 5-membered to 8-memberedunsaturated ring, can in other terms be regarded as two groups R10together forming a divalent residue comprising a chain of 3 to 6 atomsof which 0, 1 or 2 are identical or different heteroatoms selected fromthe series consisting of nitrogen, oxygen and sulfur, the terminal atomsof which are bonded to the two adjacent ring carbon atoms in Ar.Examples of such divalent residues, from any one or more of which twogroups R10 bonded to adjacent ring carbon atoms in Ar are selected inone embodiment of the invention, are the residues —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—, —CH═CH—CH═CH—, —N═CH—CH═CH—,—CH═CH—CH═N—, —CH═N—CH═CH—, —CH═CH—N═CH—, —O—CH₂—CH₂—, —CH₂—CH₂—O—,—O—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—O—,—S—CH═CH—, —CH═CH—S—, ═CH—S—CH═, —N═CH—S—, —S—CH═N—, —N═CH—O—, —O—CH═N—,—NH—CH₂—CH₂—O—, —O—CH₂—CH₂—NH—, —S—CH₂—CH₂—NH— and —NH—CH₂—CH₂—S—, whichcan all be substituted by substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl and —CN, and canthus also be present, for example, as the divalent residues —O—CF₂—O—,—O—C(CH₃)₂—O—, —S—C(Cl)═CH—, —CH═C(Cl)—S—, —N(CH₃)—CH₂—CH₂—O—,—O—CH₂—CH₂—N(CH₃)—, —S—CH₂—CH₂—N(CH₃)— and —N(CH₃)—CH₂—CH₂—S—. In oneembodiment of the invention, the ring heteroatoms which are optionallypresent in a ring formed by two groups R10 bonded to adjacent ringcarbon atoms in Ar together with the carbon atoms carrying them, areselected from the series consisting of nitrogen and oxygen, in anotherembodiment from the series consisting of oxygen and sulfur, and inanother embodiment they are oxygen atoms. In one embodiment of theinvention, the ring which can be formed by two groups R10 bonded toadjacent ring carbon atoms in Ar together with the ring carbon atomscarrying them, is a 5-membered to 7-membered, in another embodiment a5-membered to 6-membered, in another embodiment a 6-membered to7-membered, in another embodiment a 5-membered, in another embodiment a6-membered ring, in another embodiment a 7-membered ring. In oneembodiment of the invention, the ring which can be formed by two groupsR10 bonded to adjacent carbon atoms in Ar together with the carbon atomscarrying them, comprises 0 ring heteroatoms, i.e. it is a carbocyclicring, and in another embodiment it comprises 1 or 2 identical ordifferent ring heteroatoms. In one embodiment of the invention, thenumber of substituents which can be present in a ring formed by twogroups R10 bonded to adjacent ring carbon atoms in Ar together with thecarbon atoms carrying them, is 1, 2, 3 or 4, in another embodiment 1, 2or 3, in another embodiment 1 or 2, in another embodiment 1, in anotherembodiment it is 0. In one embodiment of the invention, substituentswhich can be present in a ring formed by two groups R10 bonded toadjacent ring carbon atoms in Ar together with the carbon atoms carryingthem, are selected from the series consisting of halogen, (C₁-C₄)-alkyland —CN, in another embodiment from the series consisting of halogen and(C₁-C₄)-alkyl, and in another embodiment are substituents in such a ringbonded to a ring nitrogen atom selected from the series consisting of(C₁-C₄)-alkyl.

In one embodiment of the invention, R10 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl,—O—(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl-,—N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO₂ and —CN, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22,—NO₂, —C(O)—N(R23)-R24 and —CN, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl, —N(R19)-R20,—N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO₂ and —CN, in anotherembodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-C(O)—R22, —NO₂ and —CN, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-C(O)—R22 and —CN, in anotherembodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R21)-C(O)—R22, —NO₂ and —CN, in another embodimentfrom the series consisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl,—N(R21)-C(O)—R22 and —CN, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl, —NO₂ and —CN, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl and —CN, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl and —CN, in another embodiment fromthe series consisting of halogen and (C₁-C₄)-alkyl, and in anotherembodiment from the series consisting of halogen, and in all theseembodiments two groups R10 bonded to adjacent ring carbon atoms in Ar,together with the carbon atoms carrying them, can form a 5-membered to8-membered unsaturated ring which comprises 0, 1 or 2 identical ordifferent ring heteroatoms selected from the series consisting ofnitrogen, oxygen and sulfur, and which is unsubstituted or substitutedby one or more identical or different substituents selected from theseries consisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl and —CN.

In one embodiment, R10 is selected from the series consisting ofhalogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl,—O—(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl-,—N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO₂,—C(O)—N(R23)-R24 and —CN, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl,—O—(C₃-C₇)-cycloalkyl, —O—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl-,—N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO₂ and —CN, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22,—NO₂, —C(O)—N(R23)-R24 and —CN, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl, —N(R19)-R20,—N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO₂ and —CN, in anotherembodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-C(O)—R22, —NO₂ and —CN, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-C(O)—R22 and —CN, in anotherembodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl, —N(R21)-C(O)—R22, —NO₂ and —CN, in another embodimentfrom the series consisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl,—N(R21)-C(O)—R22 and —CN, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl, —NO₂ and —CN, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl and —CN, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl and —CN, in another embodiment fromthe series consisting of halogen and (C₁-C₄)-alkyl, and in anotherembodiment from the series consisting of halogen.

In one embodiment, substituents R10 which are bonded to a ring nitrogenatom in Ar, such as in the case of a pyrrole, pyrazole or imidazole ringrepresenting Ar, are selected from the series consisting of(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl and—C(O)—N(R23)-R24, in another embodiment from the series consisting of(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl,in another embodiment from the series consisting of (C₁-C₄)-alkyl.

In one embodiment of the invention, a (C₁-C₄)-alkyl group whichrepresents R10 or is present in the group —O—(C₁-C₄)-alkyl representingR10, is a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkylgroup, in another embodiment a methyl group, where all these alkylgroups can optionally be substituted by fluorine substituents as appliesto alkyl groups in general, and also occur as a trifluoromethyl group,for example. In one embodiment of the invention, a (C₃-C₇)-cycloalkylgroup which represents R10 or is present in a group R10, is a(C₃-C₆)-cycloalkyl group, in another embodiment a (C₃-C₄)-cycloalkylgroup, in another embodiment a cyclopropyl group. In one embodiment ofthe invention, the total number of —NO₂ (nitro) groups representing R10in a compound of the formula I is not greater than 2, in anotherembodiment it is not greater than 1.

Examples of groups Ar including the optional substituents R10 on Ar,from any one or more of which Ar is selected in one embodiment of theinvention, are 2,3-dichloro-phenyl, 2,5-dichloro-phenyl,5-chloro-2-hydrazino-phenyl, 5-chloro-2-cyano-phenyl,2-cyano-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl,2-chloro-5-methoxy-phenyl, 2,5-dichloro-thiophen-3-yl,8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl,5-chloro-1,3-dimethyl-pyrazol-4-yl, naphthalen-1-yl,2,4,6-trichloro-phenyl, 5-chloro-2-fluoro-phenyl,2,4,5-trifluoro-phenyl), 2,4,5-trichloro-phenyl,5-chloro-2,4-difluoro-phenyl, 2,3,4-trichloro-phenyl,2,3,4-trifluoro-phenyl, 2-chloro-4-trifluoromethyl-phenyl,5-cyano-2-fluoro-phenyl, 2-cyano-5-methoxy-phenyl,2-cyano-5-fluoro-phenyl, 2-fluoro-5-methoxy-phenyl,4-acetylamino-2-methyl-phenyl, 2-methyl-5-nitro-phenyl,2-nitro-4-trifluoromethyl-phenyl, 2,5-difluoro-phenyl, 2-fluoro-phenyl,2-chloro-3,5-difluoro-phenyl, 2-chloro-4-fluoro-phenyl,2-chloro-4,5-difluoro-phenyl, 2-chloro-3-fluoro-phenyl and2-chloro-phenyl. In another embodiment, Ar is selected from any one ormore of the groups 2,3-dichloro-phenyl, 2,5-dichloro-phenyl,5-chloro-2-hydrazino-phenyl, 5-chloro-2-cyano-phenyl,2-cyano-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl,2-chloro-5-methoxy-phenyl, 2,5-dichloro-thiophen-3-yl,8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl,5-chloro-1,3-dimethyl-pyrazol-4-yl, naphthalen-1-yl,2,4,6-trichloro-phenyl, 5-chloro-2-fluoro-phenyl,2,4,5-trifluoro-phenyl), 2,4,5-trichloro-phenyl,5-chloro-2,4-difluoro-phenyl, 2,3,4-trichloro-phenyl,2,3,4-trifluoro-phenyl, 2-chloro-4-trifluoromethyl-phenyl,5-cyano-2-fluoro-phenyl, 2-cyano-5-methoxy-phenyl,2-cyano-5-fluoro-phenyl, 2-fluoro-5-methoxy-phenyl,4-acetylamino-2-methyl-phenyl, 2-methyl-5-nitro-phenyl, and2-nitro-4-trifluoromethyl-phenyl.

The monocyclic heterocycle which can be formed by the groups R11 and R12together with the nitrogen atom carrying them, which heterocycle is thusbonded via a ring nitrogen atom, can be 4-membered, 5-membered,6-membered or 7-membered. In one embodiment of the invention, theheterocycle formed by the groups R11 and R12 together with the nitrogenatom carrying them, is 4-membered to 6-membered, in another embodimentit is 5-membered or 6-membered, in another embodiment it is 6-membered.In one embodiment, the further ring heteroatom which is optionallypresent in a heterocycle formed by the groups R11 and R12 together withthe nitrogen atom carrying them, is selected from the series consistingof nitrogen and oxygen, in another embodiment it is a nitrogen atom, andin another embodiment it is an oxygen atom, and in another embodiment nofurther ring heteroatom is present. In one embodiment of the invention,the number of substituents selected from the series consisting offluorine and (C₁-C₄)-alkyl, which can be present in a ring formed by thegroups R11 and R12 together with the nitrogen atom carrying them, is 1,2 or 3, in another embodiment 1 or 2, in another embodiment 1. In oneembodiment of the invention, substituents which can be present in a ringformed by the groups R11 and R12 together with the nitrogen atomcarrying them, are fluorine substituents, and in another embodiment theyare (C₁-C₄)-alkyl substituents, for example methyl substituents, and inanother embodiment are substituents in such a ring bonded to a ringnitrogen atom selected from the series consisting of (C₁-C₄)-alkyl.Examples of heterocyclic groups, from any one or more of which theheterocyclic group formed by the groups R11 and R12 together with thenitrogen atom carrying them is selected in one embodiment of theinvention, are azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, and 4-methylpiperazin-1-yl.

In one embodiment of the invention, one of the groups R11 and R12 isselected from the series consisting of hydrogen and (C₁-C₄)-alkyl, andthe other is selected from the series consisting of hydrogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl,in another embodiment R11 and R12 are independently of one anotherselected from the series consisting of hydrogen, (C₁-C₄)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, and in another embodiment they arehydrogen, i.e., in this latter embodiment the group —N(R11)-R12representing R1 is the group —NH₂ (amino), or in all these embodimentsR11 and R12, together with the nitrogen atom carrying them, form amonocyclic, 4-membered to 7-membered, saturated heterocycle which, inaddition to the nitrogen atom carrying R11 and R12, comprises 0 or 1further ring heteroatom selected from the series consisting of nitrogen,oxygen and sulfur, and which is unsubstituted or substituted by one ormore identical or different substituents selected from the seriesconsisting of fluorine and (C₁-C₄)-alkyl.

In one embodiment of the invention, one of the groups R11 and R12 isselected from the series consisting of hydrogen and (C₁-C₄)-alkyl, andthe other is selected from the series consisting of hydrogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl,in another embodiment, R11 and R12 are independently of one anotherselected from the series consisting of hydrogen, (C₁-C₄)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, and in another embodiment R11 and R12 arehydrogen.

In one embodiment of the invention, R13 is selected from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and (C₁-C₃)-alkyl, in another embodimentfrom the series consisting of hydrogen and methyl, and in anotherembodiment R13 is hydrogen.

In one embodiment of the invention, R14 and R15 are independently of oneanother selected from the series consisting of (C₃-C₇)-cycloalkyl,phenyl, —(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, in anotherembodiment from the series consisting of (C₃-C₇)-cycloalkyl, phenyl,—(C₁-C₄)-alkyl-phenyl and Het, in another embodiment from the seriesconsisting of (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofphenyl and Het, and in another embodiment are one or both of R14 and R15independently of one another selected from the series consisting of(C₁-C₈)-alkyl, in another embodiment from the series consisting of(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting of—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, in another embodiment from the seriesconsisting of phenyl, in another embodiment from the series consistingof —(C₁-C₄)-alkyl-phenyl, in another embodiment from the seriesconsisting of Het, and in another embodiment from the series consistingof —(C₁-C₄)-alkyl-Het, wherein in all these embodiments phenyl and Hetall are unsubstituted or substituted by one or more identical ordifferent substituents R30.

The explanations given above with respect to a monocyclic ring which canbe formed by R11 and R12 together with the nitrogen atom carrying them,and the embodiments specified above with respect to this ring, applycorrespondingly to the monocyclic ring which can be formed by R16 andR17 together with the nitrogen atom carrying them. For example, the ringwhich can be formed by the groups R16 and R17 together with the nitrogenatom carrying them, which heterocycle is thus bonded via a ring nitrogenatom, can be 4-membered, 5-membered, 6-membered or 7-membered. In oneembodiment, the further ring heteroatom which is optionally present in aheterocycle formed by the groups R16 and R17 together with the nitrogenatom carrying them, is selected from the series consisting of nitrogenand oxygen, in another embodiment it is a nitrogen atom, and in anotherembodiment it is an oxygen atom, and in another embodiment no furtherring heteroatom is present. In one embodiment of the invention,substituents in a ring formed by the groups R16 and R17 together withthe nitrogen atom carrying them, which are bonded to a ring nitrogenatom, are, selected from the series consisting of (C₁-C₄)-alkyl.Examples of heterocyclic groups, from any one or more of which theheterocyclic group formed by the groups R16 and R17 together with thenitrogen atom carrying them is selected in one embodiment of theinvention, likewise are azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, and 4-methylpiperazin-1-yl.

In one embodiment of the invention, R16 is selected from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and (C₁-C₃)-alkyl, in another embodimentfrom the series consisting of hydrogen and methyl, and in anotherembodiment R16 is hydrogen, and in one embodiment R17 is selected fromthe series consisting of hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl, Hetand —(C₁-C₄)-alkyl-Het, in another embodiment from the series consistingof hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl and—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, in another embodiment from the seriesconsisting of hydrogen, (C₁-C₈)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from the series consisting of hydrogen and (C₁-C₈)-alkyl, inanother embodiment from the series consisting of (C₁-C₈)-alkyl, and inanother embodiment R17 is hydrogen, wherein phenyl and Het all areunsubstituted or substituted by one or more identical or differentsubstituents R30, or R16 and R17, together with the nitrogen atomcarrying them, form in these embodiments a monocyclic, 4-membered to7-membered, saturated heterocycle which, in addition to the nitrogenatom carrying R16 and R17, comprises 0 or 1 further ring heteroatomselected from the series consisting of nitrogen, oxygen and sulfur, andwhich is unsubstituted or substituted by one or more identical ordifferent substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl.

In another embodiment of the invention, R16 is selected from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and (C₁-C₃)-alkyl, in another embodimentfrom the series consisting of hydrogen and methyl, and in anotherembodiment R16 is hydrogen, and in one embodiment R17 is selected fromthe series consisting of hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl, Hetand —(C₁-C₄)-alkyl-Het, in another embodiment from the series consistingof hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl and—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, in another embodiment from the seriesconsisting of hydrogen, (C₁-C₈)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from the series consisting of hydrogen and (C₁-C₈)-alkyl, inanother embodiment from the series consisting of (C₁-C₈)-alkyl, and inanother embodiment R17 is hydrogen, wherein phenyl and Het all areunsubstituted or substituted by one or more identical or differentsubstituents R30.

In one embodiment of the invention, a (C₁-C₈)-alkyl group representingR17 is (C₁-C₄)-alkyl, in another embodiment (C₁-C₃)-alkyl, in anotherembodiment (C₁-C₂)-alkyl, in another embodiment methyl.

In one embodiment of the invention, R18 is selected from the seriesconsisting of hydrogen and (C₁-C₂)-alkyl, in another embodiment from theseries consisting of hydrogen and methyl, in another embodiment R18 ishydrogen, in another embodiment R18 is selected from the seriesconsisting (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of (C₁-C₂)-alkyl, and in another embodiment R18 is methyl.

The explanations given above with respect to a monocyclic ring which canbe formed by R11 and R12 together with the nitrogen atom carrying them,and the embodiments specified above with respect to this ring, applycorrespondingly to the monocyclic ring which can be formed by R19 andR20 together with the nitrogen atom carrying them. For example, the ringwhich can be formed by the groups R19 and R20 together with the nitrogenatom carrying them, which heterocycle is thus bonded via a ring nitrogenatom, can be 4-membered, 5-membered, 6-membered or 7-membered. In oneembodiment, the further ring heteroatom which is optionally present in aheterocycle formed by the groups R19 and R20 together with the nitrogenatom carrying them, is selected from the series consisting of nitrogenand oxygen, in another embodiment it is a nitrogen atom, and in anotherembodiment it is an oxygen atom, and in another embodiment no furtherring heteroatom is present. In one embodiment of the invention,substituents in a ring formed by the groups R19 and R20 together withthe nitrogen atom carrying them, which are bonded to a ring nitrogenatom, are, selected from the series consisting of (C₁-C₄)-alkyl.Examples of heterocyclic groups, from any one or more of which theheterocyclic group formed by the groups R19 and R20 together with thenitrogen atom carrying them is selected in one embodiment of theinvention, likewise are azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, and 4-methylpiperazin-1-yl.

In one embodiment of the invention, R19 is selected from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theserious consisting of hydrogen and (C₁-C₃)-alkyl, in another embodimentfrom the series consisting of hydrogen and methyl, and in anotherembodiment R19 is hydrogen, and in one embodiment R20 is selected fromthe series consisting of hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl, Hetand —(C₁-C₄)-alkyl-Het, in another embodiment from the series consistingof hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl and—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, in another embodiment from the seriesconsisting of hydrogen, (C₁-C₈)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from the series consisting of hydrogen and (C₁-C₈)-alkyl, inanother embodiment from the series consisting of (C₁-C₈)-alkyl, and inanother embodiment R20 is hydrogen, wherein phenyl and Het all areunsubstituted or substituted by one or more identical or differentsubstituents R30, or R19 and R20, together with the nitrogen atomcarrying them, form in these embodiments a monocyclic, 4-membered to7-membered, saturated heterocycle which, in addition to the nitrogenatom carrying R19 and R20, comprises 0 or 1 further ring heteroatomselected from the series consisting of nitrogen, oxygen and sulfur, andwhich is unsubstituted or substituted by one or more identical ordifferent substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl.

In another embodiment of the invention, R19 is selected from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theserious consisting of hydrogen and (C₁-C₃)-alkyl, in another embodimentfrom the series consisting of hydrogen and methyl, and in anotherembodiment R19 is hydrogen, and in one embodiment R20 is selected fromthe series consisting of hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl, Hetand —(C₁-C₄)-alkyl-Het, in another embodiment from the series consistingof hydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl,—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl and—(C₁-C₄)-alkyl-Het, in another embodiment from the series consisting ofhydrogen, (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl and—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, in another embodiment from the seriesconsisting of hydrogen, (C₁-C₈)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from the series consisting of hydrogen and (C₁-C₈)-alkyl, inanother embodiment from the series consisting of (C₁-C₈)-alkyl, and inanother embodiment R20 is hydrogen, wherein phenyl and Het all areunsubstituted or substituted by one or more identical or differentsubstituents R30.

In one embodiment of the invention, a (C₁-C₈)-alkyl group representingR20 is (C₁-C₄)-alkyl, in another embodiment (C₁-C₃)-alkyl, in anotherembodiment (C₁-C₂)-alkyl, in another embodiment methyl.

In one embodiment of the invention, R21 is selected from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and (C₁-C₃)-alkyl, in another embodimentfrom the series consisting of hydrogen and methyl, in another embodimentR21 is hydrogen, and in another embodiment R21 is methyl.

In one embodiment of the invention R22 is selected from the seriesconsisting of (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl and—(C₁-C₂)-alkyl-(C₃-C₆)-cycloalkyl, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl and (C₃-C₆)-cycloalkyl, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl and—(C₁-C₂)-alkyl-(C₃-C₆)-cycloalkyl, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of (C₁-C₃)-alkyl, and in another embodiment R22 is methyl.

In one embodiment of the invention, R23 and R24 are independently of oneanother selected from the series consisting of hydrogen and(C₁-C₃)-alkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₂)-alkyl, in another embodiment from the seriesconsisting of hydrogen and methyl, and in another embodiment R23 and R24are hydrogen.

In one embodiment of the invention, R30 is in any of its occurrences,independently of its other occurrences, selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl and —CN, in another embodiment fromthe series consisting of halogen, (C₁-C₄)-alkyl and —O—(C₁-C₄)-alkyl, inanother embodiment from the series consisting of halogen and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhalogen and —CN, in another embodiment from the series consisting ofhalogen. In one embodiment, a group R30 which is bonded to ring nitrogenatom in a group Het, is selected from the series consisting of(C₁-C₄)-alkyl. In one embodiment, a (C₁-C₄)-alkyl group representing R30or occurring in R30 is in any occurrence of R30, independently of otheroccurrences, selected from (C₁-C₃)-alkyl, in another embodiment from(C₁-C₂)-alkyl, and in another embodiment it is methyl.

The monocyclic group Het can be 4-membered, 5-membered, 6-membered or7-membered. In one embodiment of the invention, Het is in any of itsoccurrences, independently of its other occurrences, 4-membered,5-membered or 6-membered, in another embodiment 5-membered or6-membered, in another embodiment 5-membered, in another embodiment6-membered, in another embodiment 5-membered, 6-membered or 7-membered.In one embodiment, Het is in any of its occurrences, independently ofits other occurrences, a saturated or partially saturated heterocycle,in another embodiment a saturated heterocycle, in another embodiment asaturated or aromatic heterocycle, in another embodiment an aromaticheterocycle. In one embodiment, the ring heteroatoms in a heterocycleHet which is saturated or partially unsaturated, are selected from theseries consisting of nitrogen and oxygen, in another embodiment from theseries consisting of oxygen and sulfur. In one embodiment, the ringheteroatoms in a heterocycle Het which is aromatic, are selected fromthe series consisting of nitrogen and sulfur. In one embodiment, Hetcomprises in any of its occurrences, independently of its otheroccurrences, 1 ring heteroatom selected from the series consisting ofnitrogen, oxygen and sulfur. Examples of groups, from any one or morewhich Het is in any of its occurrences, independently of any otheroccurrence, selected in one embodiment of the invention, are oxetanylincluding oxetan-2-yl and oxetan-3-yl, tetrahydrofuranyl includingtetrahydrofuran-2-yl and tetrahydrofuran-3-yl, tetrahydropyranylincluding tetrahydropyran-2-yl, tetrahydropyran-3-yl andtetrahydropyran-4-yl, oxepanyl including oxepan-2-yl, oxepan-3-yl andoxepan-4-yl, azetidinyl including azetidin-2-yl and azetidin-3-yl,pyrrolidinyl including pyrrolidin-2-yl and pyrrolidin-3-yl, piperidinylincluding piperidin-2-yl, piperidin-3-yl and piperidin-4-yl, azepanylincluding azepan-2-yl, azepan-3-yl and azepan-4-yl, morpholinylincluding morpholin-2-yl and morpholin-3-yl, thiomorpholinyl includingthiomorpholin-2-yl and thiomorpholin-3-yl, piperazinyl includingpiperazin-2-yl, furanyl including furan-2-yl and furan-3-yl, thiophenyl(thienyl) including thiophen-2-yl and thiophen-3-yl, pyrrolyl includingpyrrol-2-yl and pyrrol-3-yl, isoxazolyl including isoxazol-3-yl,isoxazol-4-yl and isoxazol-5-yl, oxazolyl including oxazol-2-yl,oxazol-4-yl and oxazol-5-yl, thiazolyl including thiazol-2-yl,thiazol-4-yl and thiazol-5-yl, pyrazolyl including pyrazol-3-yl,pyrazol-4-yl and pyrazol-5-yl, imidazolyl including imidazol-2-yl,imidazol-4-yl and imidazol-5-yl, pyridinyl (pyridyl) includingpyridin-2-yl, pyridin-3-yl and pyridin-4-yl, pyrazinyl includingpyrazin-2-yl.

A subject of the invention are all compounds of the formula I whereinany one or more structural elements such as groups, residues,substituents and numbers are defined as in any of the specifiedembodiments or definitions of the elements, or have one or more of thespecific meanings which are mentioned herein as examples of elements,wherein all combinations of one or more definitions of compounds orelements and/or specified embodiments and/or specific meanings ofelements are a subject of the present invention. Also with respect toall such compounds of the formula I, all their stereoisomeric forms andmixtures of stereoisomeric forms in any ratio, and theirpharmaceutically acceptable salts are a subject of the presentinvention.

As an example of compounds of the invention which with respect to anystructural elements are defined as in specified embodiments of theinvention or definitions of such elements, compounds of the formula Imay be mentioned, wherein

-   Ar is selected from the series consisting of phenyl and a 5-membered    or 6-membered monocyclic aromatic heterocycle comprising 1 or 2    identical or different ring heteroatoms selected from the series    consisting of nitrogen, oxygen and sulfur and bonded via a ring    carbon atom, which are all unsubstituted or substituted by one or    more identical or different substituents R10;-   n is selected from the series consisting of 0, 1 and 2;-   R1 is selected from the series consisting of hydrogen, —N(R11)-R12,    —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14,    (C₁-C₄)-alkyl and —(C₁-C₄)-alkyl-O—R18;-   R2 is selected from the series consisting of halogen, (C₁-C₄)-alkyl    and —CN;-   R10 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20,    —N(R21)-C(O)—R22, —NO₂, —C(O)—N(R23)-R24 and —CN,-   and two groups R10 bonded to adjacent ring carbon atoms in Ar,    together with the carbon atoms carrying them, can form a 5-membered    to 7-membered unsaturated ring which comprises 0, 1 or 2 identical    or different ring heteroatoms selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of halogen, (C₁-C₄)-alkyl and    —CN;-   R11 and R12 are independently of one another selected from the    series consisting of hydrogen and (C₁-C₄)-alkyl,-   or R11 and R12, together with the nitrogen atom carrying them, form    a monocyclic, 4-membered to 6-membered, saturated heterocycle which,    in addition to the nitrogen atom carrying R11 and R12, comprises 0    or 1 further ring heteroatom selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R13 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R14 and R15 are independently of one another selected from the    series consisting of (C₃-C₇)-cycloalkyl, phenyl,    —(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, wherein phenyl    and Het all are unsubstituted or substituted by one or more    identical or different substituents R30;-   R18 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R19 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R20 is selected from the series consisting of hydrogen,    (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl and    —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl;-   or R19 and R20, together with the nitrogen atom carrying them, form    a monocyclic, 4-membered to 6-membered, saturated heterocycle which,    in addition to the nitrogen atom carrying R19 and R20, comprises 0    or 1 further ring heteroatom selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R21 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R22 is selected from the series consisting of (C₁-C₄)-alkyl and    (C₃-C₇)-cycloalkyl;-   R23 and R24 are independently of one another selected from the    series consisting of hydrogen and (C₁-C₄)-alkyl;-   R30 is selected from the series consisting of halogen, (C₁-C₄)-alkyl    and —CN;-   Het is a monocyclic, 4-membered to 7-membered, saturated, partially    unsaturated or aromatic heterocycle which comprises 1 or 2 identical    or different ring heteroatoms selected from the series consisting of    nitrogen, oxygen and sulfur, and which is bonded via a ring carbon    atom;-   wherein all cycloalkyl groups can be substituted by one or more    identical substituents selected from the series consisting of    fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

As another such example, compounds of the formula I may be mentioned,wherein

-   Ar is selected from the series consisting of phenyl and a 5-membered    or 6-membered monocyclic aromatic heterocycle comprising 1 or 2    identical or different ring heteroatoms selected from the series    consisting of nitrogen, oxygen and sulfur and bonded via a ring    carbon atom, which are all unsubstituted or substituted by one or    more identical or different substituents R10;-   n is selected from the series consisting of 0 and 1;-   R1 is selected from the series consisting of hydrogen, —N(R11)-R12,    —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14 and    (C₁-C₄)-alkyl;-   R2 is selected from the series consisting of halogen and    (C₁-C₄)-alkyl;-   R10 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20,    —N(R21)-C(O)—R22, —NO₂ and —CN,-   and two groups R10 bonded to adjacent ring carbon atoms in Ar,    together with the carbon atoms carrying them, can form a 5-membered    to 7-membered unsaturated ring which comprises 0, 1 or 2 identical    or different ring heteroatoms selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of halogen and (C₁-C₄)-alkyl;-   R11 and R12 are independently of one another selected from the    series consisting of hydrogen and (C₁-C₄)-alkyl,-   or R11 and R12, together with the nitrogen atom carrying them, form    a monocyclic, 5-membered or 6-membered, saturated heterocycle which,    in addition to the nitrogen atom carrying R11 and R12, comprises 0    or 1 further ring heteroatom selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R13 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R14 and R15 are independently of one another selected from the    series consisting of (C₃-C₇)-cycloalkyl, phenyl,    —(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, wherein phenyl    and Het all are unsubstituted or substituted by one or more    identical or different substituents R30;-   R19 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R20 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   or R19 and R20, together with the nitrogen atom carrying them, form    a monocyclic, 4-membered to 6-membered, saturated heterocycle which,    in addition to the nitrogen atom carrying R19 and R20, comprises 0    or 1 further ring heteroatom selected from the series consisting of    nitrogen, oxygen and sulfur, and which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R21 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R22 is selected from the series consisting of (C₁-C₄)-alkyl;-   R30 is selected from the series consisting of halogen, (C₁-C₄)-alkyl    and —CN;-   Het is a monocyclic, 5-membered or 6-membered, saturated, partially    unsaturated or aromatic heterocycle which comprises 1 or 2 identical    or different ring heteroatoms selected from the series consisting of    nitrogen, oxygen and sulfur, and which is bonded via a ring carbon    atom;-   wherein all cycloalkyl groups can be substituted by one or more    identical substituents selected from the series consisting of    fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

As another such example, compounds of the formula I may be mentioned,wherein

-   Ar is phenyl which is unsubstituted or substituted by one or more    identical or different substituents R10;-   n is selected from the series consisting of 0 and 1;-   R1 is selected from the series consisting of hydrogen, —N(R11)-R12,    —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14 and    (C₁-C₄)-alkyl;-   R2 is selected from the series consisting of halogen and    (C₁-C₄)-alkyl;-   R10 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20,    —N(R21)-C(O)—R22, —NO₂ and —CN,-   and two groups R10 bonded to adjacent ring carbon atoms in Ar,    together with the carbon atoms carrying them, can form a 5-membered    to 7-membered unsaturated ring which comprises 0, 1 or 2 oxygen    atoms as ring heteroatoms, and which is unsubstituted or substituted    by one or more identical or different substituents selected from the    series consisting of halogen and (C₁-C₄)-alkyl;-   R11 and R12 are independently of one another selected from the    series consisting of hydrogen and (C₁-C₄)-alkyl;-   R13 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R14 and R15 are independently of one another selected from the    series consisting of (C₃-C₇)-cycloalkyl, phenyl,    —(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, wherein phenyl    and Het all are unsubstituted or substituted by one or more    identical or different substituents R30;-   R19 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R20 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R21 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R22 is selected from the series consisting of (C₁-C₄)-alkyl;-   R30 is selected from the series consisting of halogen and    (C₁-C₄)-alkyl;-   Het is a monocyclic, 5-membered or 6-membered, saturated, partially    unsaturated or aromatic heterocycle which comprises 1 ring    heteroatom selected from the series consisting of nitrogen, oxygen    and sulfur, and which is bonded via a ring carbon atom;-   wherein all cycloalkyl groups can be substituted by one or more    identical substituents selected from the series consisting of    fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

As another such example, compounds of the formula I may be mentioned,wherein

-   Ar is selected from the series consisting of 2,3-dichloro-phenyl,    2,5-dichloro-phenyl, 5-chloro-2-hydrazino-phenyl,    5-chloro-2-cyano-phenyl, 2-cyano-5-methyl-phenyl,    2-fluoro-5-methyl-phenyl, 2-chloro-5-methoxy-phenyl,    2,5-dichloro-thiophen-3-yl,    8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl,    5-chloro-1,3-dimethyl-pyrazol-4-yl, naphthalen-1-yl,    2,4,6-trichloro-phenyl, 5-chloro-2-fluoro-phenyl,    2,4,5-trifluoro-phenyl, 2,4,5-trichloro-phenyl,    5-chloro-2,4-difluoro-phenyl, 2,3,4-trichloro-phenyl,    2,3,4-trifluoro-phenyl, 2-chloro-4-trifluoromethyl-phenyl,    5-cyano-2-fluoro-phenyl, 2-cyano-5-methoxy-phenyl,    2-cyano-5-fluoro-phenyl, 2-fluoro-5-methoxy-phenyl,    4-acetylamino-2-methyl-phenyl, 2-methyl-5-nitro-phenyl, and    2-nitro-4-trifluoromethyl-phenyl;-   n is selected from the series consisting of 0 and 1;-   R1 is selected from the series consisting of hydrogen, —N(R11)-R12,    —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14 and    (C₁-C₄)-alkyl;-   R2 is selected from the series consisting of halogen and    (C₁-C₄)-alkyl;-   R11 and R12 are independently of one another selected from the    series consisting of hydrogen and (C₁-C₄)-alkyl;-   R13 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R14 and R15 are independently of one another selected from the    series consisting of (C₃-C₇)-cycloalkyl, phenyl,    —(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, wherein phenyl    and Het all are unsubstituted or substituted by one or more    identical or different substituents R30;-   R30 is selected from the series consisting of halogen and    (C₁-C₄)-alkyl;-   Het is a monocyclic, 5-membered or 6-membered, saturated, partially    unsaturated or aromatic heterocycle which comprises 1 ring    heteroatom selected from the series consisting of nitrogen, oxygen    and sulfur, and which is bonded via a ring carbon atom;-   wherein all cycloalkyl groups can be substituted by one or more    identical substituents selected from the series consisting of    fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

As another such example, compounds of the formula I may be mentioned,wherein

-   Ar is selected from the series consisting of 2,3-dichloro-phenyl,    2,5-dichloro-phenyl, 5-chloro-2-hydrazino-phenyl,    5-chloro-2-cyano-phenyl, 2-cyano-5-methyl-phenyl,    2-fluoro-5-methyl-phenyl, 2-chloro-5-methoxy-phenyl,    2,5-dichloro-thiophen-3-yl,    8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl,    5-chloro-1,3-dimethyl-pyrazol-4-yl, naphthalen-1-yl,    5-cyano-2-fluoro-phenyl, 2-cyano-5-methoxy-phenyl,    2-cyano-5-fluoro-phenyl, 2-fluoro-5-methoxy-phenyl,    4-acetylamino-2-methyl-phenyl, 2-methyl-5-nitro-phenyl, and    2-nitro-4-trifluoromethyl-phenyl;-   n is selected from the series consisting of 0 and 1;-   R1 is selected from the series consisting of hydrogen, —N(R11)-R12,    —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14 and    (C₁-C₄)-alkyl;-   R2 is selected from the series consisting of halogen and    (C₁-C₄)-alkyl;-   R11 and R12 are independently of one another selected from the    series consisting of hydrogen and (C₁-C₄)-alkyl;-   R13 is selected from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   R14 and R15 are independently of one another selected from the    series consisting of (C₃-C₇)-cycloalkyl, phenyl,    —(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, wherein phenyl    and Het all are unsubstituted or substituted by one or more    identical or different substituents R30;-   R30 is selected from the series consisting of halogen and    (C₁-C₄)-alkyl;-   Het is a monocyclic, 5-membered or 6-membered, saturated, partially    unsaturated or aromatic heterocycle which comprises 1 ring    heteroatom selected from the series consisting of nitrogen, oxygen    and sulfur, and which is bonded via a ring carbon atom;-   wherein all cycloalkyl groups can be substituted by one or more    identical substituents selected from the series consisting of    fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

A subject of the invention also is a compound of the formula I which isselected from any of the specific compounds of the formula I which aredisclosed herein, or is any one of the specific compounds of the formulaI which are disclosed herein, irrespective thereof whether they aredisclosed as a free compound and/or as a specific salt, or apharmaceutically acceptable salt thereof, wherein the compound of theformula I is a subject of the invention in any of its stereoisomericforms or a mixture of stereoisomeric forms in any ratio. For example, asubject of the invention is a compound of the formula I which isselected from the series consisting of:

-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3-dichloro-benzenesulfonamide,-   2,5-dichloro-N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2,5-dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2,3-dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-hydrazino-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,5-dichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,3-dichloro-benzenesulfonamide,-   2,5-dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2,3-dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   5-chloro-2-fluoro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   5-chloro-2-cyano-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2-cyano-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2-fluoro-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2-chloro-5-methoxy-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-cyano-5-methyl-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-5-methoxy-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-chloro-2-cyano-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-thiophene-3-sulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-1,3-dimethyl-pyrazole-4-sulfonamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopropanecarboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]tetrahydropyran-4-carboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]piperidine-4-carboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopentanecarboxamide,-   2,3-dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclohexanecarboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-2-phenyl-acetamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]thiophene-3-carboxamide,-   4-chloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]naphthalene-1-sulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,6-trichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trifluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2,4-difluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trifluoro-benzenesulfonamide),-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide,-   5-chloro-N-[4-[3-[(5-chloro-2,4-difluoro-phenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-2,4-difluoro-benzenesulfonamide,-   5-chloro-N-[4-[3-[(5-chloro-1,3-dimethyl-pyrazol-4-yl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-1,3-dimethyl-pyrazole-4-sulfonamide,-   2,4,5-trifluoro-N-[4-[3-[(2,4,5-trifluorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-cyano-2-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-methoxy-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-fluoro-5-methoxy-benzenesulfonamide,-   1-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-3-(3-pyridyl)urea,-   1-(4-chlorophenyl)-3-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]urea,-   2-chloro-N-[4-[3-[[2-chloro-4-trifluoromethyl-phenyl]sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-4-trifluoromethyl-benzenesulfonamide,-   N-[6-[4-(1-naphthylsulfonylamino)phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]naphthalene-1-sulfonamide,-   2,4,6-trichloro-N-[4-[3-[(2,4,6-trichlorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide,-   N-[3-methyl-4-[[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]sulfamoyl]phenyl]acetamide,-   2-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-nitro-benzenesulfonamide,    and-   N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide,    or which is any one of these compounds, and its pharmaceutically    acceptable salts.

Another subject of the invention is a compound of the formula I which isselected from the series consisting of:

-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3-dichloro-benzenesulfonamide,-   2,5-dichloro-N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2,5-dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2,3-dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-hydrazino-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,5-dichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,3-dichloro-benzenesulfonamide,-   2,5-dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2,3-dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   5-chloro-2-fluoro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   5-chloro-2-cyano-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2-cyano-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2-fluoro-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   2-chloro-5-methoxy-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-cyano-5-methyl-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-5-methoxy-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-chloro-2-cyano-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-thiophene-3-sulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-1,3-dimethyl-pyrazole-4-sulfonamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopropanecarboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]tetrahydropyran-4-carboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]piperidine-4-carboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopentanecarboxamide,-   2,3-dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclohexanecarboxamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-2-phenyl-acetamide,-   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]thiophene-3-carboxamide,-   4-chloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]naphthalene-1-sulfonamide,-   5-chloro-N-[4-[3-[(5-chloro-2,4-difluoro-phenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-2,4-difluoro-benzenesulfonamide,-   5-chloro-N-[4-[3-[(5-chloro-1,3-dimethyl-pyrazol-4-yl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-1,3-dimethyl-pyrazole-4-sulfonamide,-   2,4,5-trifluoro-N-[4-[3-[(2,4,5-trifluorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-cyano-2-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-methoxy-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-fluoro-5-methoxy-benzenesulfonamide,-   1-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-3-(3-pyridyl)urea,-   1-(4-chlorophenyl)-3-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]urea,-   2-chloro-N-[4-[3-[[2-chloro-4-trifluoromethyl-phenyl]sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-4-trifluoromethyl-benzenesulfonamide,-   N-[6-[4-(1-naphthylsulfonylamino)phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]naphthalene-1-sulfonamide,-   2,4,6-trichloro-N-[4-[3-[(2,4,6-trichlorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide,-   N-[3-methyl-4-[[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]sulfamoyl]phenyl]acetamide,-   2-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-nitro-benzenesulfonamide,    and-   N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide,    or which is any one of these compounds, and its pharmaceutically    acceptable salts.

Another subject of the invention is a compound of the formula I which isselected from the series consisting of:

-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-3,5-difluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-4-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-4,5-difluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-3-fluoro-benzenesulfonamide,    and-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-benzenesulfonamide,    or which is any one of these compounds, and its pharmaceutically    acceptable salts.

In one embodiment of the invention, the compounds of the formula I aredefined as above in their generic definition or in any of the morespecific definitions or embodiments, with the proviso that the compoundof the formula I is not one of the following compounds:

-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,6-trichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trifluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2,4-difluoro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trichloro-benzenesulfonamide,-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trifluoro-benzenesulfonamide,    and-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide,    and in another embodiment the excluded compounds are excluded as the    free compounds, i.e. they are not excluded in the form of a salt    with an acid or base.

In another embodiment of the invention, the compounds of the formula Iare defined as above in their generic definition or in any of the morespecific definitions or embodiments, with the proviso that the compoundof the formula I is not a compound in which simultaneously the group Aris a phenyl group which is substituted by three identical or differenthalogen substituents, n is 0, and R1 is the group —NH₂ (amino), and theproviso that the compound of the formula I is not one of the followingcompounds:

-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide,    and-   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide,    and in another embodiment the excluded compounds are excluded as the    free compounds, i.e. they are not excluded in the form of a salt    with an acid or base.

In another embodiment of the invention, the compounds of the formula Iare defined as above in their generic definition or in any of the morespecific definitions or embodiments, with the proviso that the compoundof the formula I is not a compound in which simultaneously the group Aris selected from the series consisting of 2,4,6-trichloro-phenyl,5-chloro-2-fluoro-phenyl, 2,4,5-trichloro-phenyl,2,4,5-tri-fluoro-phenyl, 5-chloro-2,4-difluoro-phenyl,2,3,4-trichloro-phenyl, 2,3,4-trifluoro-phenyl and2-chloro-4-trifluoromethyl-phenyl, n is 0, and R1 is the group —NH₂(amino), and in another embodiment the excluded compounds are excludedas the free compounds, i.e. they are not excluded in the form of a saltwith an acid or base.

Another subject of the present invention are processes for thepreparation of the compounds of the formula I which are outlined belowand by which the compounds of the formula I and intermediates andoccurring in the course of their synthesis, and salts thereof, areobtainable. The compounds of the formula I can be prepared by utilizingprocedures and techniques which per se are known to a person skilled inthe art. In general, 1H-pyrazolo[3,4-b]pyrazine compounds of the formulaI can be prepared, for example, in the course of a convergent synthesis,by linking two or more fragments which can be derived retrosyntheticallyfrom the formula I. More specifically, suitably substituted starting1H-pyrazolo[3,4-b]pyrazine derivatives can be employed as buildingblocks in the preparation of the compounds of formula I, which can besynthesized from suitable precursor compounds, which allow theintroduction of a variety of substituents into the various positions ofthe 1H-pyrazolo[3,4-b]pyrazine system and which can be chemicallymodified further in order to finally arrive at the compound of theformula I having the desired substituent pattern. For the synthesis of1H-pyrazolo[3,4-b]pyrazines, use can also be made of procedures andtransformations which are described in the literature with respect toindazoles. As reviews in which numerous details and literaturereferences on the chemistry of indazoles and on synthetic procedures fortheir preparation can be found, J. Eiguero in Comprehensive HeterocyclicChemistry II, Eds. A. Katritzky, Ch. Rees, E. Scriven, Elsevier 1996,Vol. 3; W. Stadlbauer in Houben-Weyl, Methoden der Organischen Chemie(Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Germany1994, Vol. E8b, Hetarene; W. Stadlbauer in Houben-Weyl, Science ofSynthesis, Georg Thieme Verlag, Stuttgart, Germany 2002, Vol. 12.2,227-324, may be mentioned. The starting materials employed in thesynthesis of the compounds of the formula I are commercially availableor can be prepared according to procedures, or in analogy to procedures,described in the literature or herein. As examples of literaturearticles relating to synthetic procedures and transformations which canbe used in the synthesis of the compounds of the formula I, thefollowing may be mentioned:

-   Brown et al., Bioorg. Med. Chem. Lett. 2010, 20, 679; Knochel et    al., Chem. Commun. 2009, 37, 5615; which relate to the formation of    1H-pyrazolo[3,4-b]pyrazines from 2-acyl-3-chloro-pyrazines and    hydrazine-   US 2010/0029653; which relates to the formation of    1H-pyrazolo[3,4-b]pyrazines from 2-alkynyl-3-chloro-pyrazines and    hydrazine-   Hajos et al., J. Org. Chem. 2008, 73, 3900; Maitte et al., J.    Heterocycl. Chem. 1983, 20, 1645; which relate to the formation of    1H-pyrazolo[3,4-b]pyrazines from 2-acyl-pyrazines and hydrazines-   Stanovnik et al., Heterocycles 1982, 19, 339; Tisler et al.,    Monatshefte für Chemie, 1982, 113, 731; which relate to the    formation of 3-acylamino-1H-pyrazolo[3,4-b]pyrazines from    3-amino-2-[1,2,4]oxadiazol-2-yl-pyrazines in the presence of a base-   Stanovnik et al., Heterocycles 1982, 19, 339; Tisler et al.    Monatshefte für Chemie 1982, 113, 731; Augustynowicz-Kopec et al.,    Farmaco 2005, 60, 513; Otomasu et al., Chem. Pharm. Bull. 1984, 32,    3361; which relate to the formation    3-amino-1H-pyrazolo[3,4-b]pyrazines from 2-cyano-3-chloro-pyrazines    and hydrazines-   Guarneri et al., J. Heterocycl. Chem. 1986, 23, 585, which relates    to the transformation of 1H-6-oxa-1,2,4,7-tetraaza-inden-5-ones into    1H-pyrazolo[3,4-b]pyrazines-   US 2005/0070542; Sio et al., Farmaco Sci. 1982, 37, 116; Andaluz et    al., J. Heterocycl. Chem. 1989, 26, 949; Hofmann et al., Journal    fuer Praktische Chemie 1990, 332, 584; Townsend et al., Tetrahedron    Lett. 2004, 45, 4105; which relate to the formation of    1H-pyrazolo[3,4-b]pyrazines by reaction of diamino-pyrazoles and    amino-nitro-pyrazoles with 2-keto-carboxylic acids and    1,2-dicarbonyl compounds.

In one synthetic approach for the preparation of compounds of theformula I, a compound of the formula II and a compound of the formulaIII are reacted to give a compound of the formula IV, which can alreadybe the final compound of the formula I, or which is converted into thedesired final compound of the formula I.

More specifically, in particular in case the group R1 in the compound ofthe formula I is hydrogen or an optionally substituted alkyl group,according to this approach a compound of the formula II is obtained byreacting a compound of the formula V with a hydrazine of the formula VI,the obtained compound of the formula II and a compound of the formulaIII are reacted to give a compound of the formula IV, and the compoundof the formula IV converted into the compound of the formula I.

In an alternative approach, a compound of the formula IV can be obtainedby first reacting a compound of the formula V with a compound of theformula III to give a compound of the formula VII, and then reacting thecompound of the formula VII with a hydrazine of the formula VI.

In another synthetic approach for the preparation of compounds of theformula I, in particular in case of compounds in which the group R1 isbonded via a nitrogen atom to the 1H-pyrazolo[3,4-b]pyrazine ringsystem, specifically in case of the preparation of compounds in which R1is an amino group, a compound of the formula X is obtained by reacting acompound of the formula VIII with a hydrazine of the formula VI, and theobtained compound of the formula IX and a compound of the formula IIIare reacted to give a compound of the formula X, which can already bethe final compound of the formula I, or which is converted into thedesired final compound of the formula I.

In an alternative approach, a compound of the formula X can be obtainedby first reacting a compound of the formula VIII with a compound of theformula III to give a compound of the formula XI, and then reacting thecompound of the formula XI with a hydrazine of the formula VI.

The groups R1 and R2 and the number n in the compounds of the formulaeII, III, IV, V, VII, X and XI are defined as in the compounds of theformula I, and additionally can functional groups be present inprotected form or in the form of a precursor group which is subsequentlyconverted into the final group. The group G1 in the compounds of theformulae II, V, VIII and IX is a leaving group which can be replaced ina Suzuki-type reaction or Stille-type reaction, such as a halogen atom,in particular bromine or chlorine, or a sulfonyloxy group, in particulartrifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy ortosyloxy(4-methylbenzenesulfonyloxy). The group G2 in the compounds offormulae V, VII, VIII and XI can be identical to or different from thegroup G1 and is a leaving group, such as a halogen atom, in particularbromine or chlorine, or a sulfonyloxy group, in particulartrifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy ortosyloxy. The group G3 in the compounds of formulae II, IV, VI, IX and Xcan be hydrogen, and in this case the compound of the formula VI thus behydrazine, or it can be a protecting group which is suitable forprotecting a ring nitrogen atom in the 1H-pyrazolo[3,4-b]pyrazine ringsystem or similar ring systems such as the pyrazole ring system, forexample, like a tetrahydropyran-2-yl group, a tert-butoxycarbonyl group,an ethoxycarbonyl group, a benzyl group or a substituted benzyl grouplike a 4-methoxybenzyl group or a 2,5-dimethoxybenzyl group. The groupG4 in the compounds of formulae III, IV, VII, X and XI can already bethe desired final sulfonamide group of the formula Ar—S(O)₂—NH—, inwhich Ar is defined as in the compounds of the formula I andadditionally can functional groups be present in protected form or inthe form of a precursor group which is subsequently converted into thefinal group. G4 can also be a group which can be converted into thedesired final sulfonamide group of the formula Ar—S(O)₂—NH— at anappropriate stage of the synthesis, for example in the compounds of theformulae IV and X, such as a precursor group like a nitro group whichcan be reduced to an amino group, or a protected amino group like atert-butoxycarbonylamino group or a benzyloxycarbonylamino group whichcan be deprotected to an amino group, or a free amino group, and theamino group then be converted into the group Ar—S(O)₂—NH— by reactionwith a sulfonyl chloride under standard conditions. The group G5 in thecompounds of formula III is a trialkylstannyl group, for example atri((C₁-C₄)-alkyl)stannyl group, or a boronic acid group (—B(OH)₂) or aboronic acid ester group or cyclic boronic acid ester group, for examplea —B(O—(C₁-C₄)-alkyl)₂ group or a4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl group, in particular aboronic acid group or a boronic acid ester group or cyclic boronic acidester group, which allows performing a Suzuki-type reaction orStille-type reaction for coupling the compounds of the formulae II, V,VIII and IX with the compounds of the formula III. The startingcompounds in the synthesis of the compounds of the formula I can also beemployed, and the intermediates obtained and/or employed, in the form ofsalts, for example acid addition salts in case of basic compounds. Theintermediates can also be present in another tautomeric form, forexample in the case of the compounds of the formulae II or IX in whichG3 is hydrogen, which can be present in the form of the respective2H-pyrazolo[3,4-b]pyrazine derivatives in which the mobile hydrogenatom, which in the compound of the formula II is bonded to the ringnitrogen atom in position 1 of the pyrazolo[3,4-b]pyrazine ring system,is bonded to the ring nitrogen atom in position 2 of thepyrazolo[3,4-b]pyrazine ring system.

The reaction of compounds of the formulae V, VII, VIII and XI with ahydrazine of the formula VI is generally carried out in a protic oraprotic solvent such as water, an alcohol like methanol, ethanol,trifluoroethanol, n-propanol, isopropanol, butanol, isobutanol,tert-butanol, 2-methylbutan-2-ol, 3-methyl-3-pentanol,3-ethyl-3-pentanol, a hydrocarbon like benzene, toluene, xylene,mesitylene, a nitrile like acetonitrile, an ether like tetrahydrofuranor diglyme (di(2-methoxyethyl)ether), an amide like dimethylformamide,N-methylpyrrolidinone, dimethylacetamide, a sulfoxide likedimethylsulfoxide, or an amine like pyridine, or in a mixture ofsolvents, at temperatures from about 20° C. to about 200° C., forexample at temperatures from about 80° C. to about 120° C. The reactiontime generally is from about 30 minutes to about 48 hours, for examplefrom about 5 hours to about 16 hours, depending on the particulars ofthe specific case and the chosen temperature range. Instead of usingconventional heating, the reaction can also be carried out in amicrowave oven utilizing microwave radiation at temperatures from about60° C. to about 200° C., for example at temperatures from about 80° C.to about 120° C. In such case, the reaction time generally is from about5 minutes to about 12 hours, for example from about 10 minutes to about3 hours, depending on the particulars of the specific case and thechosen temperature range. The compound of the formula VI can be employedin free form, i.e., not in the form of a salt, for example in the formof a solution in a solvent like ethanol or isopropanol, or in the formof an acid addition salt, for example in the form of a salt withhydrochloric acid. In case a salt is employed, it can be transformedinto the free form prior to the reaction or in situ with an organic orinorganic base such as an amine like triethylamine,ethyldiisopropylamine, N-methylmorpholine or1,8-diazabicyclo[5.4.0]unde-7-ene, an alkoxide like sodium methoxide,sodium ethoxide, potassium methoxide, potassium tert-butoxide, an amidelike lithium diisopropylamide or sodium amide, or an alkali metalcarbonate like sodium carbonate, potassium carbonate or cesiumcarbonate, for example.

The reaction of compounds of the formulae II, V, VIII and IX with acompound of the formula III in which G5 is a boronic acid group or aboronic acid ester group or cyclic boronic acid ester group, is aSuzuki-type reaction, and is generally carried out in the presence ofcatalytic palladium compound, for example a palladium(II) salt likepalladium(II) acetate or palladium(II) chloride, which can be employedin the presence of a phosphine such as1,1′-bis(diphenylphosphino)ferrocene, tricyclohexylphosphine ortriphenylphosphine, or a palladium complex such astetrakis(triphenylphosphine)palladium(0),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride,palladium(0) bis(tri-tert-butylphosphine) orbis(triphenylphosphine)palladium(II) chloride, and favorably in thepresence of a base, for example an alkali metal carbonate or alkalimetal phosphate like cesium carbonate, sodium carbonate or tripotassiumphosphate, in an inert solvent, such as a hydrocarbon like benzene,toluene or xylene, or an ether like tetrahydrofuran (THF), dioxane or1,2-dimethoxyethane (DME), or water, or a mixture of solvents, attemperatures from about 20° C. to about 200° C., for example attemperatures from about 80° C. to about 120° C. The reaction timegenerally is from about 30 minutes to about 48 hours, for example from30 minutes to about 16 hours, depending on particulars of the specificcase and the chosen temperature range. Except for the use of water assolvent, these explanations on the Suzuki-type reactions substantiallyapply also to reactions with compounds of the formula III in which G5 isa trialkylstannyl group, i.e. Stille-type reactions.

Further, in order to obtain the desired 1H-pyrazolo[3,4-b]pyrazinecompound of the formula I, the functional groups introduced into thering system during the 1H-pyrazolo[3,4-b]pyrazine synthesis can bechemically modified by a variety of reactions and thus the desiredgroups obtained. For example, a 1H-pyrazolo[3,4-b]pyrazine carrying ahydrogen atom in position 3 can also be obtained by saponification andsubsequent decarboxylation of 1H-pyrazolo[3,4-b]pyrazines carrying anester group in this position. Halogen atoms can be introduced, forexample, according to well-known procedures described in the literature.A fluorination of the aromatic substructures of compounds of the formulaI can be carried out using a variety of reagents including, for example,N-fluoro-2,4,6-trimethylpyridinium triflate. A chlorination,bromination, or iodination can be accomplished by reaction with theelemental halogens or, for example, by use of N-bromosuccinimide,N-chlorosuccinimide or N-iodosuccinimide and many other reagents wellknown to the person skilled in the art. By selective halogen/metalexchange, or metalation by selective hydrogen/metal exchange, andsubsequent reaction with a wide range of electrophiles, varioussubstituents can be introduced using procedures which are know per se.Among others, halogen atoms, hydroxy groups after conversion into thetriflate or nonaflate, for example, or primary amino groups afterconversion into the diazonium salt, can directly, or after conversion tothe corresponding stannane or boronic acid or boronic acid ester,converted into a variety of other groups like, for example, —CN, —CF₃,—C₂F₅ and ether, acid, amide, amine, alkyl or aryl groups. For suchconversions, favorably use can also be made of reactions mediated bytransition metals, such as palladium or nickel catalysts or coppersalts, as are described in F. Diederich, P. Stang, Metal-catalyzedCross-coupling Reactions, Wiley-VCH, 1998; M. Beller, C. Bolm,Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji,Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem.1998, 110, 2154; B. Yang, S. Buchwald, J. Organomet. Chem. 1999, 576,125; T. Sakamoto, K. Ohsawa, J. Chem. Soc. Perkin Trans I, 1999, 2323;D. Nichols, S. Frescas, D. Marona-Lewicka, X. Huang, B. Roth, G.Gudelsky, J. Nash, J. Med. Chem., 1994, 37, 4347; P. Lam, C. Clark, S.Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett.,1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M. Winters, TetrahedronLett. 1998, 39, 2933; V. Farina, V. Krishnamurthy, W. Scott, The StilleReaction, Wiley, 1994; F. Qing et al., J. Chem. Soc. Perkin Trans.11997, 3053; S. Buchwald et al., J. Am. Chem. Soc. 2001, 123, 7727; S.Kang et al. Synlett 2002, 3, 427; S. Buchwald et al., Organic Lett.2002, 4, 581; T. Fuchikami et al., Tetrahedron Lett. 1991, 32, 91; Q.Chen et al., Tetrahedron Lett. 1991, 32, 7689; M. R. Netherton, G. C.Fu, Topics in Organometallic Chemistry 2005, 14, 85-108; A. F. Littke,G. F. Fu, Angew. Chem. Int. Ed. 2002, 41, 4176-4211; A. R. Muci, S. L.Buchwald, Topics in Current Chemistry 2002, 219, 131-209, for example.Nitro groups can be reduced to amino groups with various reducingagents, such as sulfides, dithionites, complex hydrides or by catalytichydrogenation. A reduction of a nitro group may also be carried outsimultaneously with a reaction performed on another functional group,for example when reacting a group like a cyano group with hydrogensulfide or when hydrogenating a group. Amino groups can then be modifiedaccording to standard procedures, for example alkylated by reaction withoptionally substituted alkyl halogenides like chlorides, bromides oriodides or sulfonyloxy compounds like tosyloxy, mesyloxy ortrifluoromethylsulfonyloxy compounds, preferably in the presence of abase like potassium carbonate, cesium carbonate, sodium hydride orpotassium tert-butoxide, or by reductive amination of carbonylcompounds, or acylated by reaction with activated carboxylic acidderivatives such as acid chlorides, anhydrides, activated esters orothers or by reaction with carboxylic acids in the presence of anactivating agent, or sulfonylated by reaction with sulfonyl chlorides.Ester groups can be hydrolyzed to the corresponding carboxylic acidswhich after activation can then be reacted with amines under standardconditions. Furthermore, ester or acid groups can be reduced to thecorresponding alcohols by many standard procedures, and the resultinghydroxy compounds alkylated. Ether groups, for example benzyloxy groupsor other easily cleavable ether groups, can be cleaved to give hydroxygroups which can then be reacted with a variety of agents, for exampleetherification agents or activating agents allowing replacement of thehydroxy group by other groups. A hydroxy group can also be convertedinto a leaving group and reacted with various reaction partners underthe well-known conditions of the Mitsunobu reaction (O. Mitsunobu,Synthesis 1981, 1), or by further procedures (cf. A. Tunoori, D. Dutta,G. Gunda, Tetrahedron Lett. 39 (1998) 8751; J. Pelletier, S. Kincaid,Tetrahedron Lett. 41 (2000) 797; D. L. Hughes, R. A. Reamer, J. J.Bergan, E. J. J. Grabowski, J. Am. Chem. Soc. 110 (1998) 6487; D. J.Camp, I. D. Jenkins, J. Org. Chem. 54 (1989) 3045; D. Crich, H. Dyker,R. J. Harris, J. Org. Chem. 54 (1989) 257).

The mentioned reactions for the conversion of functional groups are, ingeneral, extensively described in textbooks of organic chemistry like M.Smith, J. March, March's Advanced Organic Chemistry, Wiley-VCH, 2001,and in Houben-Weyl, Methoden der Organischen Chemie (Methods of OrganicChemistry), Georg Thieme Verlag, Stuttgart, Germany; Organic Reactions,John Wiley & Sons, New York; R. C. Larock, Comprehensive OrganicTransformations, Wiley-VCH, 2^(nd) ed (1999); B. Trost, I. Fleming(eds.), Comprehensive Organic Synthesis, Pergamon, 1991; A. Katritzky,C. Rees, E. Scriven, Comprehensive Heterocyclic Chemistry II, ElsevierScience, 1996; for example, in which details on the reactions andprimary source literature can be found. Due to the fact that in thepresent case the functional groups occur in 1H-pyrazolo[3,4-b]pyrazinecompounds, it may in certain cases become necessary to specificallyadapt reaction conditions or choose specific reagents from a variety ofreagents that can in principle be employed in a conversion reaction, orotherwise take specific measures for achieving a desired conversion, forexample to use protection group techniques, as applies in general and isknown to the person skilled in the art.

In the course of the preparation of the compounds of the formula I itcan generally be advantageous or necessary in order to reduce or preventundesired reactions or side reactions in the respective synthesis steps,to block functional groups temporarily by protecting groups suited tothe specific synthesis problem, or to have them present, or introducethem, in the form of precursor groups, and later convert them into thedesired functional groups. Such strategies are well known to a personskilled in the art and are described, for example, in Greene and Wuts,Protective Groups in Organic Synthesis, Wiley, 1991, or P. Kocienski,Protecting Groups, Thieme 1994.

Examples of precursor groups are cyano groups and nitro groups. Thecyano group can, in a later step, be transformed by hydrolysis intocarboxylic acid derivatives or by reduction into aminomethyl groups.Nitro groups can be transformed by reduction like catalytichydrogenation into amino groups. Examples of protective groups which maybe mentioned, are benzyl protective groups, for example benzyl ethers ofhydroxy compounds and benzyl esters of carboxylic acids, from which thebenzyl group can be removed by catalytic hydrogenation in the presenceof a palladium catalyst, tert-butyl protective groups, for exampletert-butyl esters of carboxylic acids, from which the tert-butyl groupcan be removed by treatment with trifluoroacetic acid, acyl protectivegroups, for example ester and amides of hydroxy compounds and aminocompounds, which can be cleaved again by acidic or basic hydrolysis, oralkoxycarbonyl protective groups, for example tert-butoxycarbonylderivatives of amino compounds, which can be cleaved again by treatmentwith trifluoroacetic acid. Compounds of the formula I can also beprepared by solid phase techniques. In such a synthetic approach, thesolid phase may also be regarded as having the meaning of a protectinggroup, and cleavage from the solid phase as removal of the protectivegroup. The use of such techniques is known to a person skilled in theart (cf. Burgess, K. (Ed.), Solid Phase Organic Synthesis, New York,Wiley, 2000). For example, a phenolic hydroxy group can be attached to atrityl-polystyrene resin, which serves as a protecting group, and themolecule cleaved from the resin by treatment with trifluoroacetic acidor another acid at a later stage of the synthesis.

As is usual and applies to all reactions performed in the course of thesynthesis of a compound of the formula I, appropriate details of theconditions applied in a specific preparation process, including thesolvent, a base or acid, the temperature, the order of addition, themolar ratios and other parameters, are routinely chosen by the skilledperson in view of the characteristics of the starting compounds and thetarget compound and the other particularities of the specific case. Asis also known by the skilled person, not all processes described hereinwill in the same way be suitable for the preparation of all compounds ofthe formula I and their intermediates, and adaptations have to be made.In all processes for the preparation of the compounds of the formula I,workup of the reaction mixture and the purification of the product isperformed according to customary methods known to the skilled personwhich include, for example, quenching of a reaction mixture with water,adjustment of a certain pH, precipitation, extraction, drying,concentration, crystallization, distillation and chromatography. Asfurther examples of methods applicable in the synthesis of the compoundsof the formula I, microwave assistance for speeding-up, facilitating orenabling reactions, as described by P. Lidstrom, J. Tierney, B. Wathey,J. Westman, Tetrahedron, 57 (2001), 9225, for example, may be mentioned,and modern separation techniques like preparative high pressure liquidchromatography (HPLC), which can be used for separating mixtures ofpositional isomers which may occur in any reactions. Also for thecharacterization of the products customary methods are used, such asNMR, IR and mass spectroscopy.

Another subject of the present invention are the novel startingcompounds and intermediates occurring in the synthesis of the compoundsof the formula I, including the compounds of the formulae II, III, IV,V, VII, VIII, IX, X and XI, wherein the groups R1, R2, G1, G2, G3, G4and G5 and the number n are defined as above, in any of theirstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,and their salts, and their use as synthetic intermediates or startingcompounds. All general explanations, specifications of embodiments anddefinitions of numbers and groups given above with respect to thecompounds of the formula I apply correspondingly to the saidintermediates and starting compounds. A subject of the invention are inparticular the novel specific starting compounds and intermediatesdescribed herein. Independently thereof whether they are described as afree compound and/or as a specific salt, they are a subject of theinvention both in the form of the free compounds and in the form oftheir salts, and if a specific salt is described, additionally in theform of this specific salt.

The compounds of the present invention are SGK inhibitors, which arecapable of inhibiting an exaggerated, or inappropriate, activity of SGKin pathological conditions and are therefore suitable for theprophylaxis and therapy of the diseases mentioned above and below. Inparticular, they are highly active inhibitors of the SGK-1 enzyme. Theyare selective SGK-1 inhibitors inasmuch as they do not substantiallyinhibit or promote the activity of other enzymes and receptors whoseactivation or inhibition is not desired. The activity of the compoundsof the formula I can be determined, for example, in the assays describedbelow or in other in vitro, ex vivo or in vivo assays known to theperson skilled in the art. For example, the ability of the compounds toinhibit the SGK enzyme may be measured by methods similar to thosedescribed in D. Perrin et al., Expert Opin. Drug Discov. (2010) 5,51-63, and by the assay described below. With respect to SGK-1inhibitory activity, one embodiment of the invention comprises compoundswhich have an IC₅₀ value of <1 μM, in another embodiment of <0.1 μM, inanother embodiment of <0.01 μM, for SGK-1 inhibition as determined inthe assay described below, and which in a further embodiment do notsubstantially influence the activity of other enzymes and receptorswhose inhibition or activation is not desired. The ability of thecompounds to inhibit the SGK-1 mediated glycogen synthase kinase 3beta(GSK3beta) phosphorylation in a cellular setting may be measured bymethods similar to those described by H. Sakoda et al. J. Biol. Chem.2003, 278, 25802-25807, and by the method described below. The abilityof the compounds to inhibit SGK1 dependent activation of epithelial Na⁺channel (ENaC) currents in cell monolayers may be measured by methodssimilar to those described by D. Alvarez de la Rosa et al., Am. J.Physiol. Cell Physiol. 2003, 284, 404-414; D. Alvarez de la Rosa et al.,J. Gen. Physiol. 2004, 124, 395-407; and by the assay described below.The inappropriate SGK-1 activity referred to herein is any SGK-1activity that deviates from the expected normal SGK-1 activity.Inappropriate SGK-1 activity may take the form of, for example, anabnormal increase in activity, or an aberration in the timing and/orcontrol of SGK-1 activity. Such inappropriate activity may result then,for example, from overexpression or mutation of the protein kinaseleading to inappropriate or uncontrolled activation. As SGK-1inhibitors, the compounds of the formula I and their pharmaceuticallyacceptable salts are generally suitable for the prophylaxis and/ortherapy of conditions in which the inappropriate activity of SGK-1enzyme plays a role or has an undesired extent, or which can favorablybe influenced by inhibiting the SGK-1 enzyme or decreasing the activity,or for the prevention, alleviation or cure of which an inhibition ofSGK-1 or a decrease in the activity is desired by the physician.

Because of their pharmacological properties, the compounds of thepresent invention are suitable for the treatment of all disorders in theprogression of which an enhanced activity of SGK enzyme is involved.These include the indications described in the introduction. Theinvention relates in particular to the use of a compound of the formulaI or a pharmaceutically acceptable salt thereof for the treatment ofdegenerative joint disorders and degenerative cartilage changesincluding osteoarthritis, osteoarthrosis, rheumatoid arthritis,spondylosis, chondrolysis following joint trauma and prolonged jointimmobilization after meniscus or patella injuries or ligament tears,connective tissue disorders such as collagenoses, periodontal disorders,wound-healing disturbances, diabetes including diabetes mellitus,diabetic nephropathy, diabetic neuropathy, diabetic angiopathy andmicroangiopathy, obesity, metabolic syndrome (dyslipidaemia), systemicand pulmonary hypertension, cerebral infarctions, cardiovasculardiseases including cardiac fibrosis after myocardial infarction, cardiachypertrophy and heart failure, arteriosclerosis, renal diseasesincluding glomerulosclerosis, nephrosclerosis, nephritis, nephropathyand electrolyte excretion disorder, any type of fibrosis andinflammatory processes including liver cirrhosis, lung fibrosis,fibrosing pancreatitis, rheumatism, arthritis, gout, Crohn's disease,chronic bronchitis, radiation fibrosis, sclerodermatitis, cysticfibrosis, scar formation, Alzheimer's disease, pain including acute painlike pain following injuries, post-operative pain, pain in associationwith an acute attack of gout and acute pain following jaw-bone surgeryinterventions, and chronic pain like pain associated with chronicmusculoskeletal diseases, back pain, pain associated with osteoarthritisor rheumatoid arthritis, pain associated with inflammation, amputationpain, pain associated with multiple sclerosis, pain associated withneuritis, pain associated with carcinomas and sarcomas, pain associatedwith AIDS, pain associated with chemotherapy, trigeminus neuralgia,headache, migraine cephalalgia, neuropathic pains, post-herpes zosterneuralgia, chronic disorders of the locomotor system such asinflammatory, immunologically or metabolically related acute and chronicarthritides, arthropathies, myalgias and disturbances of bonemetabolism, peptic ulcers, especially in forms that are triggered bystress, tinnitus, bacterial infections, glaucoma, cataracts,coagulopathies including dysfibrinogenaemia, hypoproconvertinaemia,haemophilia B, Stuart-Prower defect, prothrombin complex deficiency,consumption coagulopathy, fibrinolysis, immunokoagulopathy or complexcoagulopathies, and to the use in tumor therapy including inhibition oftumor growth and tumor metastases, the use in anti-infective therapy,the use for increasing the learning ability and attention, the use forcounteracting cellular aging and stress and thus increasing lifeexpectancy and fitness in the elderly, and the use in states of neuronalexcitability including epilepsy. The treatment of diseases is to beunderstood herein as generally meaning both the therapy of existingpathological changes or malfunctions of the organism or of existingsymptoms with the aim of relief, alleviation or cure, and theprophylaxis or prevention of pathological changes or malfunctions of theorganism or of symptoms in humans or animals which are susceptiblethereto and are in need of such a prophylaxis or prevention, with theaim of a prevention or suppression of their occurrence or of anattenuation in the case of their occurrence. For example, in patientswho on account of their disease history are susceptible to myocardialinfarction, by means of the prophylactic or preventive medicinaltreatment the occurrence or re-occurrence of a myocardial infarct can beprevented or its extent and sequelae decreased. The treatment ofdiseases can occur both in acute cases and in chronic cases.

The compounds of the formula I and their pharmaceutically acceptablesalts can therefore be used in animals, in particular in mammals andspecifically in humans, as a pharmaceutical or medicament on their own,in mixtures with one another, or in the form of pharmaceuticalcompositions. A subject of the present invention also are the compoundsof the formula I and their pharmaceutically acceptable salts for use asa pharmaceutical. A subject of the present invention also arepharmaceutical compositions and medicaments which comprise at least onecompound of the formula I and/or a pharmaceutically acceptable saltthereof as an active ingredient, in an effective dose for the desireduse, and a pharmaceutically acceptable carrier, i.e. one or morepharmaceutically innocuous, or nonhazardous, vehicles and/or excipients,and optionally one or more other pharmaceutical active compounds.

A subject of the present invention also are the compounds of the formulaI and their pharmaceutically acceptable salts for use in the treatmentof the diseases mentioned above or below, including the treatment of anyone of the mentioned diseases, for example the treatment of degenerativejoint disorders, degenerative cartilage changes, diabetes,cardiovascular diseases, fibrosis, inflammatory processes, pain, tumorsor cerebral infarctions, wherein treatment of diseases comprises theirtherapy and prophylaxis as mentioned above, or for use as an inhibitorof serum and glucocorticoid regulated kinase (SGK). A subject of thepresent invention also are the use of the compounds of the formula I andtheir pharmaceutically acceptable salts for the manufacture of amedicament for the treatment of the diseases mentioned above or below,including the treatment of any one of the mentioned diseases, forexample the treatment of degenerative joint disorders, degenerativecartilage changes, diabetes, cardiovascular diseases, fibrosis,inflammatory processes, pain, tumors or cerebral infarctions, whereintreatment of diseases comprises their therapy and prophylaxis asmentioned above, or a medicament for inhibition of serum andglucocorticoid regulated kinase (SGK). A subject of the presentinvention also are methods for the treatment of the diseases mentionedabove or below, including the treatment of any one of the mentioneddiseases, for example the treatment of degenerative joint disorders,degenerative cartilage changes, diabetes, cardiovascular diseases,fibrosis, inflammatory processes, pain, tumors or cerebral infarctions,wherein treatment of diseases comprises their therapy and prophylaxis asmentioned above, and a method for inhibiting serum and glucocorticoidregulated kinase (SGK), which comprise administering an efficaciousamount of at least one compound of the formula I and/or apharmaceutically acceptable salt thereof to a human or an animal whichis in need thereof.

The compounds of the formula I and their pharmaceutically acceptablesalts, and pharmaceutical compositions and medicaments comprising them,can be administered enterally, for example by oral or rectaladministration in the form of pills, tablets, lacquered tablets, coatedtablets, granules, hard and soft gelatin capsules, solutions, syrups,emulsions, suspensions, aerosol mixtures or suppositories, orparenterally. Parenteral administration can be carried out, for example,intravenously, intraarticularly, intraperitoneally, intramuscularly orsubcutaneously, in the form of injection solutions or infusionsolutions, microcapsules, implants or rods, or percutaneously,transdermally or topically, for example in the form of ointments,solutions or tinctures, or in other ways, for example in the form ofaerosols or nasal sprays. The preferred form of administration dependson the particulars of the specific case.

Pharmaceutical formulations adapted for transdermal administration canbe administered as plasters for extended, close contact with theepidermis of the recipient. For topical administration, formulationssuch as ointments, creams, suspensions, lotions, powders, solutions,pastes, gels, sprays, aerosols or oils can be used. For the treatment ofthe eye or other external tissue, for example mouth and skin, suitableformulations are topical ointments or creams, for example. In the caseof ointments, the active ingredient can be employed either with aparaffinic or a water-miscible cream base. Alternatively, the activeingredient can be formulated to give a cream with an oil-in-water creambase or a water-in-oil base. Pharmaceutical formulations adapted fortopical application to the eye include eye drops, in which the activeingredient is dissolved or suspended in a suitable carrier, inparticular an aqueous solvent.

The pharmaceutical compositions according to the invention are preparedin a manner known per se and familiar to the person skilled in the artby admixing one or more pharmaceutically acceptable inert inorganicand/or organic vehicles and excipients with one or more compounds of theformula I and/or pharmaceutically acceptable salts thereof, and bringingthem into a suitable form for dosage and administration, which can thenbe used in human medicine or veterinary medicine. For the production ofpills, tablets, coated tablets and hard gelatin capsules it is possibleto use, for example, lactose, cornstarch or derivatives thereof, talc,stearic acid or its salts. For the production of gelatin capsules andsuppositories fats, waxes, semisolid and liquid polyols, natural orhardened oils, for example, can be used. For the production ofsolutions, for example injection solutions, or of emulsions or syrupswater, saline, alcohols, glycerol, polyols, sucrose, invert sugar,glucose, vegetable oils, for example, can be used, and for theproduction of microcapsules, implants or rods copolymers of glycolicacid and lactic acid, for example, can be used. The pharmaceuticalcompositions normally contain from about 0.5% to 90% by weight of thecompounds of the formula I and/or their pharmaceutically acceptablesalts. The amount of the active ingredient of the formula I and/or itspharmaceutically acceptable salts in the pharmaceutical compositionsnormally is from about 0.5 mg to about 1000 mg, preferably from about 1mg to about 500 mg per unit dose. Depending on the kind of thepharmaceutical composition and other particulars of the specific case,the amount may deviate from the indicated ones

In addition to the active ingredients of the formula I and/or theirpharmaceutically acceptable salts and to vehicles, or carriersubstances, the pharmaceutical compositions can contain excipients, orauxiliaries or additives, such as, for example, fillers, disintegrants,binders, lubricants, wetting agents, stabilizers, emulsifiers,preservatives, sweeteners, colorants, flavorings, aromatizers,thickeners, diluents, buffer substances, solvents, solubilizers, agentsfor achieving a depot effect, salts for altering the osmotic pressure,coating agents or antioxidants. They can also contain two or morecompounds of the formula I, and/or their pharmaceutically acceptablesalts. In case a pharmaceutical composition contains two or morecompounds of the formula I, the selection of the individual compoundscan aim at a specific overall pharmacological profile of thepharmaceutical composition. For example, a highly potent compound with ashorter duration of action may be combined with a long-acting compoundof lower potency. The flexibility permitted with respect to the choiceof substituents in the compounds of the formula I allows a great deal ofcontrol over the biological and physico-chemical properties of thecompounds and thus allows the selection of such desired compounds.

When using the compounds of the formula I, the dose can vary within widelimits and, as is customary and is known to the physician, is to besuited to the individual conditions in each individual case. It depends,for example, on the specific compound employed, on the nature andseverity of the disease to be treated, on the mode and the schedule ofadministration, or on whether an acute or chronic condition is treatedor whether prophylaxis is carried out. An appropriate dosage can beestablished using clinical approaches known to the person skilled in theart. In general, the daily dose for achieving the desired results in anadult weighing about 75 kg is from about 0.01 mg/kg to about 100 mg/kg,preferably from about 0.1 mg/kg to about 50 mg/kg, in particular fromabout 0.1 mg/kg to about 10 mg/kg, in each case in mg per kg of bodyweight. The daily dose can be divided, in particular in the case of theadministration of relatively large amounts, into several, for example 2,3 or 4, part administrations. As usual, depending on individual behaviorit may be necessary to deviate upwards or downwards from the daily doseindicated.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of the SGK enzyme. For suchuse, for example in pharmaceutical research involving the SGK enzyme,the compounds may be provided in a commercial kit. For example, acompound of the present invention can be used as a reference in an assayto compare its known activity to a compound with an unknown activity.Furthermore, the compounds of the formula I can be used as synthesisintermediates for the preparation of other compounds, in particular ofother pharmaceutical active compounds, which may be obtained from thecompounds of the formula I by introduction of substituents ormodification of functional groups, for example.

The following examples illustrate the present invention.

EXAMPLES

When in the final step of the synthesis of an example compound an acidsuch as trifluoroacetic acid or acetic acid was used, for example whentrifluoroacetic acid was employed to remove an acid-labile protectinggroup containing a tert-butyl group, or when a compound was purified bychromatography using an eluent which contained such an acid, in somecases, depending on the work-up procedure, for example the details of afreeze-drying process, the compound was obtained partially or completelyin the form of a salt of the acid used, for example in the form of thesalt with acetic acid salt or trifluoroacetic acid salt. In the names ofthe example compounds and the structural formulae such containedtrifluoroacetic acid or acetic acid is not specified.

The prepared compounds were in general characterized by spectroscopicdata and chromatographic data, in particular mass spectra (MS) and/ornuclear magnetic resonance (NMR) spectra. In the NMR characterization,the chemical shift 8 (in ppm), the number of hydrogen atoms (H), thecoupling constant J (in Hz) and the multiplicity (s: singlet, d:doublet, dd: double doublet, t: triplet, m: multiplet; br: broad) of thepeaks are given. In the MS characterization, the mass number (m/e) ofthe peak of the molecular ion (M) or of a related ion such as the ion(M+1), i.e. the protonated molecular ion (M+H), or the ion (M−1), whichwas formed depending on the ionization method used, is given. Generally,the ionization method was electrospray ionization (ES+ or ES−).

Abbreviations

-   DCM Dichloromethane-   dioxane [1,4]Dioxane-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EtOAc Ethyl acetate-   iPrOH Isopropanol-   MeCN Acetonitrile-   RT Room temperature (20° C. to 25° C.)-   TFA Trifluoroacetic acid

Example 1N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3-dichloro-benzenesulfonamide

(i)2,3-Dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide

The title compound was prepared by adding 2,3-dichloro-benzenesulfonylchloride (11.2 g) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (10.0 g) toa reaction vessel containing a magnetic stirring bar, followed by 200 mldry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for20 h before being cooled on an ice-bath and quenched with 1M aqueoussodium hydroxide solution. The organic phase was separated and theaqueous phase acidified with 2M aqueous hydrochloric acid and extractedthree times with EtOAc. The combined organic phases were washed withbrine and dried over sodium sulfate and evaporated to afford the crudeproduct. Purification by flash chromatography on silica gel using amixture of EtOAc and heptane as the eluent afforded2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamideas a colorless solid after evaporation of the solvents under reducedpressure. Yield: 15.11 g (77%).

MS (ES−): m/e=426.1 (M−H).

(ii)2,3-Dichloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)phenyl]benzenesulfonamide

2,3-Dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide(5.78 g) was added to a reaction vessel containing a magnetic stirringbar together with 3,5-dichloro-pyrazine-2-carbonitrile (2.35 g),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride(Pd(dppf)₂Cl₂) (791 mg) and cesium carbonate (13.2 g), followed by 100ml dioxane and 10 ml water, and the mixture heated to 100° C. understirring. After 3 h the reaction mixture was cooled to RT and quenchedwith a saturated aqueous sodium bicarbonate solution (100 ml) andextracted with EtOAc (3×200 ml). The combined aqueous phases were driedover sodium sulfate, filtered and evaporated to afford the crude productas a brown oil. Purification by flash chromatography on silica gel usinga mixture of EtOAc and heptane as the eluent afforded2,3-dichloro-N-[4-(6-chloro-5-cyano-pyrazin-2yl)-phenyl]-benzenesulfonamideas a light brown foam after evaporation of the solvents under reducedpressure. Yield: 4.32 g (73%).

MS (ES−): m/e=436.0 (M−H).

(iii)N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3-dichloro-benzenesulfonamide

2,3-Dichloro-N-[4-(6-chloro-5-cyano-pyrazin-2yl)-phenyl]-benzenesulfonamide(1.0 g) was suspended in a mixture of 5 ml iPrOH and 5 ml 35% hydrazinein water at RT and heated to 120° C. by microwave irradiation for 20 minunder stirring in a sealed vessel. The reaction mixture was left to coolto RT. The precipitate was filtered off and washed with water to givethe title compound as a yellow solid after drying under vacuum. Yield:536 mg (54%).

¹H-NMR (DMSO-d₆): δ (ppm)=5.67 (br s, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.58(t, J=8.0 Hz, 1H), 7.93 (dd, J=1.4, 8.0 Hz, 1H), 8.06 (d, J=8.8 Hz, 2H),8.11 (dd, J=1.5, 8.0 Hz, 1H), 8.86 (s, 1H), 12.30 (s, 1H).

MS (ES+): m/e=435.2 (M+H), chloro pattern.

Example 22,5-Dichloro-N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamidehydrochloride

(i)2,5-Dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide

To a solution of 10 g of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine in 100 mlDCM and 4 ml pyridine, 11.6 g of 2,5-dichloro-benzenesulfonyl chloridewere added, and the reaction mixture was stirred for 16 h at RT. Then,the solvents were removed under reduced pressure and the crude productwas purified by chromatography on silica gel eluting with a gradient ofn-heptane/EtOAc. The fractions containing the product were combined andthe solvent evaporated under reduced pressure. Yield: 17.9 g.

(ii)2,5-Dichloro-N-[4-(6-chloro-5-formyl-pyrazin-2-yl)-phenyl]-benzenesulfonamide

A solution of 100 mg of 3,5-dichloro-pyrazine-2-carbaldehyde, 241 mg2,5-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamideand 552 mg of cesium carbonate in 3.4 ml of dioxane and 0.6 ml of waterwas purged with argon. Then, 33 mg of1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride were addedand the reaction mixture was heated to 100° C. After 40 min, thereaction mixture was cooled to RT and diluted with water. Afterfiltration through a chem Elut® cartridge by eluting with EtOAc, thesolvents were removed under reduced pressure. The crude product waspurified by chromatography on silica gel eluting with a gradient ofn-heptane/EtOAc and finally methanol. The fractions containing theproduct were combined and the solvent evaporated under reduced pressure.Yield: 90 mg.

(iii)2,5-Dichloro-N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

To a solution of 90 mg of2,5-dichloro-N-[4-(6-chloro-5-formyl-pyrazin-2-yl)-phenyl]-benzenesulfonamidein 0.7 ml isopropanol 0.7 ml of a hydrazine solution (35% inisopropanol) were added and the reaction mixture was heated for 20 minto 120° C. by using microwave irradiation (Biotage Initiator™apparatus). The reaction mixture was cooled to RT and diluted withacetic acid (20%). The precipitated product was collected by filtrationand purified by preparative HPLC (C18 reversed phase column, elutionwith a water/MeCN gradient with 0.1% TFA). The fractions containing theproduct were lyophilized to yield the title compound in the form of itssalt with trifluoroacetic acid as a solid, which was dissolved in 1 mlof a water/acetonitrile mixture. 0.5 ml of a 1 M aqueous hydrochloricacid was added and the solution was again lyophilized to yield the titlecompound in the form of2,5-dichloro-N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamidehydrochloride. Yield: 5.2 mg.

MS (ES+): m/e=420.2 (M+H), chloro pattern.

Example 32,5-Dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamidehydrochloride

(i)2,5-Dichloro-N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzenesulfonamide

To a solution of 1.5 g of2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in 17 mlDCM and 0.5 ml pyridine, 1.5 g of 2,5-dichloro-benzenesulfonyl chloridewere added, and the reaction mixture was stirred for 16 h at RT. Thenthe solvents were removed under reduced pressure and the crude productwas purified by chromatography on silica gel eluting with a gradient ofn-heptane/EtOAc. The fractions containing the product were combined andthe solvent evaporated under reduced pressure. Yield: 2.2 g.

(ii)2,5-Dichloro-N-[4-(6-chloro-5-formyl-pyrazin-2-yl)-2-fluoro-phenyl]benzenesulfonamide

A solution of 100 mg of 3,5-dichloro-pyrazine-2-carbaldehyde, 252 mg2,5-dichloro-N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzenesulfonamideand 552 mg of cesium carbonate in 3.4 ml of dioxane and 0.6 ml of waterwas purged with argon. Then, 33 mg of1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride were addedand the reaction mixture was heated to 100° C. After 6 h the reactionmixture was cooled to RT and diluted with water. After filtrationthrough a chem Elut® cartridge by eluting with EtOAc the solvents wereremoved under reduced pressure. The crude product was purified bychromatography on silica gel eluting with a gradient of n-heptane/EtOAcand finally methanol. The fractions containing the product were combinedand the solvent evaporated under reduced pressure. Yield: 180 mg.

(iii)2,5-Dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

To a solution of 120 mg of2,5-dichloro-N-[4-(6-chloro-5-formyl-pyrazin-2-yl)-2-fluoro-phenyl]benzenesulfonamidein 0.9 ml isopropanol 0.9 ml of a hydrazine solution (35% inisopropanol) were added and the reaction mixture was heated for 20 minto 120° C. by using microwave irradiation (Biotage Initiator™apparatus). The reaction mixture was cooled to RT and diluted withacetic acid (20%). The precipitated product was collected by filtration.The crude product was purified by preparative HPLC (C18 reversed phasecolumn, elution with a water/MeCN gradient with 0.1% TFA). The fractionscontaining the product were lyophilized to yield the pure product in theform of its salt with trifluoroacetic acid as a solid, which wasdissolved in 1 ml of a water/acetonitrile mixture. 0.5 ml of a 1 Maqueous hydrochloric acid was added and the solution was againlyophilized to yield the title compound in the form of2,5-dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamidehydrochloride. Yield: 2.2 mg.

MS (ES+): m/e=438.2 (M+H), chloro pattern.

Example 42,3-Dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 3, employing 2,3-dichlorobenzenesulfonyl chloride instead of2,5-dichloro-benzenesulfonyl chloride.

MS (ES+): m/e=438.1 (M+H), chloro pattern.

Example 5N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-benzenesulfonamide

The title compound was prepared in 22% yield according to the proceduredescribed in example 1, employing 2,5-dichloro-benzenesulfonyl chlorideinstead of 2,3-dichloro-benzenesulfonyl chloride as starting material.The following modification was made. The crude reaction mixture wasevaporated to dryness, redissolved in DMF and purified by preparativeHPLC (C18 reversed phase column, elution with a water/MeCN gradient with0.1% TFA). The fractions containing the product were lyophilized toyield the title compound in the form of its salt with trifluoroaceticacid.

¹H-NMR (DMSO-d₆): δ (ppm)=7.28 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.6 Hz,1H), 7.75 (dd, J=2.5, 8.6 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 8.09 (d,J=8.8 Hz, 2H), 8.89 (s, 1H), 11.13 (s, 1H).

MS (ES+): m/e=434.9 (M+H), chloro pattern.

Example 6N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-benzenesulfonamide

The title compound was prepared in 6% yield according to the proceduredescribed in example 1, employing 5-chloro-2-fluoro-benzenesulfonylchloride instead of 2,3-dichloro-benzenesulfonyl chloride and2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamineinstead of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamineas starting material. The following modification was made. The crudereaction mixture was evaporated to dryness, redissolved in DMF andpurified by preparative HPLC (C18 reversed phase column, elution with awater/MeCN gradient with 0.1% TFA). The fractions containing the productwere lyophilized to yield the title compound in the form of its saltwith trifluoroacetic acid.

MS (ES+): m/e=437.0 (M+H), chloro pattern.

Example 7N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,5-dichloro-benzenesulfonamide

The title compound was prepared in 5% yield according to the proceduresdescribed in example 1, employing 2,5-dichloro-benzenesulfonyl chlorideinstead of 2,3-dichloro-benzenesulfonyl chloride and2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamineinstead of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamineas starting material. The following modification was made. The crudereaction mixture was evaporated to dryness, redissolved in DMF andpurified by preparative HPLC (C18 reversed phase column, elution with awater/MeCN gradient with 0.1% TFA). The fractions containing the productwere lyophilized to yield the title compound in the form of its saltwith trifluoroacetic acid.

MS (ES+): m/e=452.9 (M+H), chloro pattern.

Example 8N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-hydrazino-benzenesulfonamide

The title product was isolated as a by-product in the synthesis ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide.

MS (ES+): m/e=431.0 (M+H), chloro pattern.

Example 9N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,3-dichloro-benzenesulfonamide

The title compound was prepared in 4% yield according to the proceduredescribed in example 1, employing2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamineinstead of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamineas starting material. The following modification was made. The crudereaction mixture was evaporated to dryness, redissolved in DMF andpurified by preparative HPLC (C18 reversed phase column, elution with awater/MeCN gradient with 0.1% TFA). The fractions containing the productwere lyophilized to yield the title compound in the form of its saltwith trifluoroacetic acid.

MS (ES+): m/e=452.9 (M+H), chloro pattern.

Example 102,3-Dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

(i) 1-(3,5-Dichloro-pyrazin-2-yl)-ethanol

3,5-Dichloro-pyrazine-2-carbaldehyde (5.0 g) was dissolved in drytetrahydrofuran (100 ml) in a reaction vessel equipped with a magneticstirring bar under an argon atmosphere. The solution was cooled on anice-bath before slow addition of 10.3 ml methylmagnesium bromidesolution (3M in tetrahydrofuran), keeping the internal temperature inthe reaction vessel below 5° C. After the addition the cooling bath wasremoved and the reaction mixture stirred for another 10 min. Then thereaction mixture was quenched with a saturated aqueous sodiumbicarbonate solution (100 ml) and extracted with EtOAc (3×200 ml). Thecombined aqueous phases were dried over sodium sulfate, filtered andevaporated to afford 1-(3,5-dichloro-pyrazin-2-yl)-ethanol as a darkbrown oil. Yield: 5.23 g (96%).

(ii) 1-(3,5-Dichloro-pyrazin-2-yl)-ethanone

5 g of 1-(3,5-dichloro-pyrazin-2-yl)-ethanol obtained in step (i) weredissolved in dry DCM (100 ml) at RT in a reaction vessel containing amagnetic stirring bar and 80.7 ml Dess-Martin periodinane(1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) solution(15% in DCM), and the mixture stirred for 30 min before the reaction wasquenched with a saturated aqueous sodium bicarbonate solution (100 ml)and extracted with EtOAc (3×200 ml). The combined organic phases weredried over sodium sulfate, filtered and evaporated to afford the crudeproduct as a brown oil. Purification by flash chromatography on silicagel using a mixture of EtOAc and heptane as the eluent afforded1-(3,5-dichloro-pyrazin-2-yl)-ethanone as a colorless oil afterevaporation of the solvents under reduced pressure. Yield: 1.9 g (38%).

(iii)N-[4-(5-Acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamide

1-(3,5-Dichloro-pyrazin-2-yl)-ethanone (200 mg) and2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide(448.3 mg), prepared as in example 1, was added to a reaction vesselcontaining a magnetic stirring bar together with1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (61 mg) andcesium carbonate (1.0 g), followed by 9 ml dioxane and 1 ml water, andthe mixture heated to 100° C. under stirring. After 2 h the reactionmixture was cooled to RT and quenched with a saturated aqueous sodiumbicarbonate solution (30 ml) and extracted with EtOAc (3×30 ml). Thecombined organic phases were dried over sodium sulfate, filtered andevaporated to afford the crude product as a brown oil-Purification byflash chromatography on silica gel using a mixture of EtOAc and heptaneas the eluent affordedN-[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamideas a colorless solid after evaporation of the solvents under reducedpressure. Yield: 230 mg (48%).

(iv)2,3-Dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

N-[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamide(230 mg) was suspended in a mixture of 2 ml iPrOH and 2 ml 35% hydrazinein water at RT and heated to 120° C. by microwave irradiation (BiotageInitiator™ apparatus) for 20 min under stirring in a sealed vessel. Thereaction mixture was left to cool to RT, quenched with a saturatedaqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc(3×30 ml). The combined organic phases were dried over sodium sulfate,filtered and evaporated to afford the crude product. Purification byrecrystallisation from an acetone-water mixture afforded the titlecompound as a pale yellow solid after drying under vacuum. Yield: 81.6mg (38%).

¹H-NMR (DMSO-d₆): δ (ppm)=2.54 (s, 3H), 7.28 (d, J=8.8 Hz, 2H), 7.59 (t,J=8.0 Hz, 1H), 7.94 (dd, J=1.5, 8.1 Hz, 1H), 8.10 (d, J=8.8 Hz, 2H),8.13 (dd, J=1.5, 8.0 Hz, 1H), 9.07 (s, 1H), 11.18 (s, 1H), 13.57 (s,1H).

MS (ES+): m/e=434.0 (M+H), chloro pattern.

Example 112,5-Dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

The title compound was prepared in 5% yield according to the proceduredescribed in example 10, employing 2,5-dichloro-benzenesulfonyl chlorideinstead of 2,3-dichloro-benzenesulfonyl chloride as starting material.The following modification was made. The crude reaction mixture wasevaporated to dryness, redissolved in DMF and purified by preparativeHPLC (C18 reversed phase column, elution with a water/MeCN gradient with0.1% TFA). The fractions containing the product were lyophilized toyield the title compound in the form of its salt with trifluoroaceticacid.

¹H-NMR (DMSO-d₆): δ (ppm)=2.55 (s, 3H), 7.29 (d, J=8.8 Hz, 2H), 7.70 (d,J=8.5 Hz, 1H), 7.76 (dd, J=2.5, 8.5 Hz, 1H), 8.09 (d, J=2.5 Hz, 1H),8.12 (d, J=8.8 Hz, 2H), 9.08 (s, 1H), 11.17 (s, 1H), 13.57 (br, 1H).

MS (ES+): m/e=434.1 (M+H), chloro pattern.

Example 125-Chloro-2-fluoro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

The title compound was prepared in 9% yield according to the proceduredescribed in example 10, employing 5-chloro-2-fluoro-benzenesulfonylchloride instead of 2,3-dichloro-benzenesulfonyl chloride as startingmaterial. The following modification was made. The crude reactionmixture was evaporated to dryness, redissolved in DMF and purified bypreparative HPLC (C18 reversed phase column, elution with a water/MeCNgradient with 0.1% TFA). The fractions containing the product werelyophilized to yield the title compound in the form of its salt withtrifluoroacetic acid.

¹H-NMR (DMSO-d₆): δ (ppm)=2.55 (s, 3H), 7.31 (d, J=8.6 Hz, 2H), 7.53(dd, J=8.6, 9.2 Hz, 1H), 7.80 (m, 1H), 7.89 (dd, J=2.7, 6.0 Hz, 1H),8.14 (d, J=8.6 Hz, 2H), 9.09 (s, 1H), 11.15 (s, 1H), 13.58 (br, 1H).

MS (ES+): m/e=418.1 (M+H), chloro pattern.

Example 135-Chloro-2-cyano-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

(i) [4-(5-Acetyl-6-chloro-pyrazin-2-yl)-phenyl]-carbamic acid tert-butylester

1-(3,5-Dichloro-pyrazin-2-yl)-ethanone (2.2 g), prepared as described inexample 10, and (4-tert-butoxycarbonyl-aminophenyl)boronic acid (2.7 g),was added to a reaction vessel containing a magnetic stirring bartogether with 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (674 mg) and cesium carbonate (11.2 g), followed by 100 mldioxane and 10 ml water, and the mixture heated to 100° C. understirring. After 1 h the reaction mixture was cooled to RT and quenchedwith a saturated aqueous sodium bicarbonate solution (50 ml) andextracted with EtOAc (3×100 ml). The combined organic phases were driedover sodium sulfate, filtered and evaporated to afford the crude productas a dark brown oil. Purification by flash chromatography on silica gelusing a mixture of EtOAc and heptane as the eluent afforded[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-carbamic acid tert-butylester as a colorless solid after evaporation of the solvents underreduced pressure. Yield: 2.44 g (61%).

(ii) [4-(3-Methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acidtert-butyl ester

[4-(5-Acetyl-6-chloro-pyrazin-2-yl)-phenyl]-carbamic acid tert-butylester (2.18 g) was suspended in a mixture of 21 ml iPrOH and 21 ml 35%hydrazine in water at RT and heated to 120° C. by microwave irradiationfor 20 min under stirring in a sealed vessel. The reaction mixture wasleft to cool to RT, quenched with a saturated aqueous sodium bicarbonatesolution (10 ml) and extracted with EtOAc (3×30 ml). The combinedorganic phases were dried over sodium sulfate, filtered and evaporatedto afford the crude product. Purification by trituration in boilingEtOAc and subsequent filtration afforded[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acidtert-butyl ester as a yellow solid. Yield: 1.42 g (70%).

(iii)5-Chloro-2-cyano-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

To a reaction vessel containing a magnetic stirring bar and 179 mg[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acidtert-butyl ester was added 3 ml 4N hydrogen chloride in dioxanesolution, and the mixture stirred at RT. After 2 h the reaction mixturewas evaporated to dryness under reduced pressure and the residueredissolved in 3 ml pyridine, and 131 mg5-chloro-2-cyano-benzenesulfonyl chloride was added and the mixtureheated to 100° C. in a sealed vessel. After 30 min the reaction mixturewas cooled and evaporated to dryness, redissolved in DMF and purified bypreparative HPLC (C18 reversed phase column, elution with a water/MeCNgradient with 0.1% TFA). The fractions containing the product werelyophilized to yield the title compound in the form of its salt withtrifluoroacetic acid.

Yield: 24 mg (10%).

¹H-NMR (DMSO-d₆): δ (ppm)=2.55 (s, 3H), 7.31 (d, J=8.8 Hz, 2H), 7.97(dd, J=2.2, 8.3 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H),8.16 (d, J=8.8 Hz, 2H), 9.10 (s, 1H), 11.25 (s, 1H), 13.58 (br, 1H).

MS (ES+): m/e=425.2 (M+H), chloro pattern.

Example 142-Cyano-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

The title compound was prepared in 21% yield according to the proceduredescribed in example 13, employing 2-cyano-5-methyl-benzenesulfonylchloride instead of 5-chloro-2-cyano-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=2.47 (s, 3H), 2.55 (s, 3H), 7.29 (d, J=8.7 Hz,2H), 7.32 (d, J=8.6 Hz, 1H), 7.46-7.51 (m, 1H), 7.72 (dd, J=2.1, 7.1 Hz,1H), 8.10 (d, J=8.7 Hz, 2H), 9.07 (s, 1H), 10.93 (s, 1H), 13.55 (br,1H).

MS (ES+): m/e=405.3 (M+H).

Example 152-Fluoro-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

The title compound was prepared in 14% yield according to the proceduredescribed in example 13, employing 2-fluoro-5-methyl-benzenesulfonylchloride instead of 5-chloro-2-cyano-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=2.34 (s, 3H), 2.55 (s, 3H), 7.31 (d, J=8.6 Hz,2H), 7.53 (dd, J=8.6, 9.2 Hz, 1H), 7.80 (m, 1H), 7.89 (dd, J=2.7, 6.0Hz, 1H), 8.14 (d, J=8.6 Hz, 2H), 9.09 (s, 1H), 11.15 (s, 1H), 13.58 (br,1H).

MS (ES+): m/e=398.2 (M+H).

Example 162-Chloro-5-methoxy-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide

The title compound was prepared in 14% yield according to the proceduredescribed in example 13, employing 2-chloro-5-methoxy-benzenesulfonylchloride instead of 5-chloro-2-cyano-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=2.54 (s, 3H), 3.82 (s, 3H), 7.21 (dd, J=3.1,8.7 Hz, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.59 (d,J=3.1 Hz, 1H), 8.10 (d, J=8.8 Hz, 2H), 9.07 (s, 1H), 10.99 (s, 1H),13.55 (br, 1H).

MS (ES+): m/e=430.2 (M+H), chloro pattern.

Example 17N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-cyano-5-methyl-benzenesulfonamide

(i) [4-(6-Chloro-5-cyano-pyrazin-2-yl)-phenyl]-carbamic acid tert-butylester

(4-tert-Butoxycarbonyl-aminophenyl)boronic acid pinacol ester (8.26 g)was added to a reaction vessel containing a magnetic stirring bartogether with 3,5-dichloro-pyrazine-2-carbonitrile (5.0 g),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.68 g)and cesium carbonate (28.1 g), followed by 100 ml dioxane and 10 mlwater, and the mixture heated to 100° C. under stirring. After 1 h thereaction mixture was cooled to RT and quenched with a saturated aqueoussodium bicarbonate solution (100 ml) and extracted with EtOAc (3×200ml). The combined organic phases were dried over sodium sulfate,filtered and evaporated to afford the crude product as a brown oil whichwas purified by flash chromatography on silica gel using a mixture ofEtOAc and heptane as the eluent. The obtained product was recrystallizedfrom methyl tert-butyl ether to afford[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-carbamic acid tert-butylester as a pale yellow solid after drying under vacuum. Yield: 6.92 g(73%).

(ii) [4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acidtert-butyl ester

[4-(6-Chloro-5-cyano-pyrazin-2-yl)-phenyl]-carbamic acid tert-butylester (1.0 g) was suspended in a mixture of 10 ml iPrOH and 10 ml 35%hydrazine in water at RT and heated to 120° C. by microwave irradiationfor 70 min under stirring in a sealed vessel. The reaction mixture wasleft to cool to RT, and the precipitate was filtered off and washed withwater to afford[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acidtert-butyl ester as a yellow solid after drying under vacuum. Yield: 815mg (83%).

(iii)N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-cyano-5-methyl-benzenesulfonamide

To a reaction vessel containing a magnetic stirring bar and 180 mg[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acidtert-butyl ester was added 3 ml 4N hydrogen chloride in dioxane solutionand the mixture stirred at RT. After 2 h the reaction mixture wasevaporated to dryness under reduced pressure and the residue redissolvedin 3 ml pyridine and 131 mg 2-cyano-5-methyl-benzenesulfonyl chloridewas added and the mixture heated to 100° C. in a sealed vessel. After 1h the reaction mixture was cooled and evaporated to dryness, redissolvedin DMF and purified by preparative HPLC (C18 reversed phase column,elution with a water/MeCN gradient with 0.1% TFA). The fractionscontaining the product were lyophilized to yield the title compound inthe form or its salt with trifluoroacetic acid salt. Yield: 58 mg (20%).

MS (ES+): m/e=406.2 (M+H).

Example 18N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-5-methoxy-benzenesulfonamide

The title compound was prepared in 22% yield according to the proceduredescribed in example 17, employing 2-chloro-5-methoxy-benzenesulfonylchloride instead of 2-cyano-5-methyl-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=3.82 (s, 3H), 7.22 (dd, J=3.0, 8.7 Hz, 1H),7.27 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 7.58 (d, J=3.1 Hz, 1H),8.07 (d, J=8.8 Hz, 2H), 8.87 (s, 1H), 10.98 (s, 1H), 13.52 (br, 1H).

MS (ES+): m/e=431.1 (M+H), chloro pattern.

Example 19N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide

To a solution of 500 mg of6-(4-amino-phenyl)-1H-pyrazolo[3,4-b]pyrazin-3-ylamine hydrochloride and397 mg of 2-fluoro-5-methyl-benzenesulfonyl chloride in 4 ml DCM, 0.16ml pyridine were added and the reaction mixture was stirred for 16 h atRT. Then, the solvents were removed under reduced pressure and the crudeproduct was purified by chromatography on silica gel eluting with agradient of n-heptane/EtOAc. The fractions containing the product werecombined and the solvent evaporated under reduced pressure. Yield: 220mg.

MS (ES+): m/e=399.2 (M+H).

Example 20N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-chloro-2-cyano-benzenesulfonamide

The title compound was prepared according to the procedure described inexample 17, employing 5-chloro-2-cyano-benzenesulfonyl chloride insteadof 2-cyano-5-methyl-benzenesulfonyl chloride as starting material.

MS (ES⁺): m/e=426.1 (M+H), chloro pattern.

Example 21N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-thiophene-3-sulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2,5-dichlorothiophene-3-sulfonyl chloride insteadof 2-fluoro-5-methyl-benzenesulfonyl chloride.

¹H-NMR (DMSO-d₆): δ (ppm)=7.30 (d, J=8.8 Hz, 2H), 7.41 (s, 1H), 8.14 (d,J=8.8 Hz, 2H), 8.91 (s, 1H), 11.07 (s, 1H), 12.3 (br, 1H).

MS (ES+): m/e=441.1 (M+H), chloro pattern.

Example 22N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonyl chlorideinstead of 2-fluoro-5-methyl-benzenesulfonyl chloride.

¹H-NMR (DMSO-d₆): δ (ppm)=2.13 (t, J=5.6 Hz, 2H), 4.20 (t, J=5.6 Hz,2H), 4.25 (t, J=5.6 Hz, 2H), 7.21 (s, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.60(s, 1H), 8.07 (d, J=8.8 Hz, 2H), 8.87 (s, 1H), 10.89 (s, 1H), 12.33 (br,1H).

MS (ES+): m/e=473.2 (M+H), chloro pattern.

Example 23N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-1,3-dimethyl-pyrazole-4-sulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 5-chloro-1,3-dimethyl-pyrazole-4-sulfonyl chlorideinstead of 2-fluoro-5-methyl-benzenesulfonyl chloride.

¹H-NMR (DMSO-d₆): δ (ppm)=2.30 (s, 3H), 3.72 (s, 3H), 7.25 (d, J=8.8 Hz,2H), 8.09 (d, J=8.8 Hz, 2H), 8.90 (s, 1H), 10.81 (s, 1H), 12.30 (br,1H).

MS (ES+): m/e=419.1 (M+H), chloro pattern.

Example 242,3-Dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide

(i)N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide

To a solution of 500 mg of6-(4-amino-phenyl)-1H-pyrazolo[3,4-b]pyrazin-3-ylamine hydrochloride and397 mg of 2-fluoro-5-methyl-benzenesulfonyl chloride in 4 ml DCM, 0.16ml pyridine were added and the reaction mixture was stirred for 16 h atRT. Then, the solvents were removed under reduced pressure and the crudeproduct was purified by chromatography on silica gel eluting with agradient of n-heptane/EtOAc. The fractions containing the product werecombined and the solvent evaporated under reduced pressure. Yield: 220mg.

(ii)2,3-Dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide

To a solution of 70 mg ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamidein 0.5 ml pyridine, 13 mg of 2,3-dichloro-benzoyl chloride were addedand the reaction mixture was stirred for 16 h at RT. Then, the reactionmixture was diluted with water and filtered through a chem Elut®cartridge by eluting with EtOAc. After removal of the solvents underreduced pressure the crude product was purified by preparative HPLC (C18reversed phase column, elution with a water/MeCN gradient with 0.1%TFA). The fractions containing the product were lyophilized to yield thetitle compound in the form of its salt with trifluoroacetic acid. Yield:5 mg.

¹H-NMR (DMSO-d₆): δ (ppm)=2.33 (s, 3H), 7.29 (d, J=8.8 Hz, 2H), 7.32 (m,1H), 7.48 (m, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.73 (m, 1H), 7.80 (d, J=8.8Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 9.29 (s, 1H), 10.95 (s, 1H), 12.40 (br,1H).

MS (ES+): m/e=571.3 (M+H), chloro pattern.

Example 25N-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]tetrahydropyran-4-carboxamide

The title compound was prepared by adapting the procedures described inexample 24, employing tetrahydropyran-4-carbonyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES+): m/e=511.2 (M+H).

Example 26N-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]piperidine-4-carboxamide

The title compound was prepared by adapting the procedures described inexample 24, employing piperidine-4-carbonyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES+): m/e=510.3 (M+H).

Example 27N-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopentanecarboxamide

The title compound was prepared by adapting the procedures described inexample 24, employing cyclopentanecarbonyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES−): m/e=493.4 (M−H).

Example 28N-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopropanecarboxamide

The title compound was prepared by adapting the procedures described inexample 24, employing cyclopropanecarbonyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES+): m/e=467.3 (M+H).

Example 29N-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclohexanecarboxamide

The title compound was prepared by adapting the procedures described inexample 24, employing cyclohexanecarbonyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES+): m/e=509.4 (M+H).

Example 30N-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-2-phenyl-acetamide

The title compound was prepared by adapting the procedures described inexample 24, employing 2-phenylacetyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES+): m/e=517.4 (M+H).

Example 31N-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]thiophene-3-carboxamide

The title compound was prepared by adapting the procedures described inexample 24, employing thiophene-3-carbonyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES+): m/e=509.3 (M+H).

Example 324-Chloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide

The title compound was prepared by adapting the procedures described inexample 24, employing 4-chloro-benzoyl chloride instead of2,3-dichloro-benzoyl chloride.

MS (ES+): m/e=537.3 (M+H), chloro pattern.

Example 33N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]naphthalene-1-sulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing naphthalene-1-sulfonyl chloride instead of2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=417.2 (M+H).

Example 34N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,6-trichloro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2,4,6-trichlorobenzenesulfonyl chloride instead of2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=470.1 (M+H), chloro pattern.

Example 35N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 1, employing 5-chloro-2-fluoro-benzenesulfonyl chloride insteadof 2,3-dichloro-benzenesulfonyl chloride as starting material. Thefollowing modification was made. The crude reaction mixture wasevaporated to dryness, redissolved in DMF and purified by preparativeHPLC (C18 reversed phase column, elution with a water/MeCN gradient with0.1% TFA). The fractions containing the product were lyophilized toyield the title compound in the form of its salt with trifluoroaceticacid.

¹H-NMR (DMSO-d₆): δ (ppm)=7.27 (d, J=8.8 Hz, 2H), 7.55 (t, J=8.7 Hz,1H), 7.81 (m, 1H), 7.88 (m, 1H), 8.10 (d, J=8.8 Hz, 2H), 8.91 (s, 1H),11.10 (s, 1H).

MS (ES+): m/e=419.0 (M+H), chloro pattern.

Example 36N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2-chloro-4-trifluoromethyl-benzenesulfonylchloride instead of 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=469.2 (M+H), chloro pattern.

Example 37N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trifluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2,4,5-trifluoro-benzenesulfonyl chloride insteadof 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=421.1 (M+H).

Example 38N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trichloro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2,4,5-trichloro-benzenesulfonyl chloride insteadof 2-fluoro-5-methyl-benzenesulfonyl chloride.

¹H-NMR (DMSO-d₆): δ (ppm)=7.28 (d, J=8.6 Hz, 2H), 8.09 (d, J=8.6 Hz,2H), 8.24 (s, 1H), 8.87 (s, 1H), 11.18 (s, 1H), 12.30 (br, 1H).

MS (ES+): m/e=469.0 (M+H), chloro pattern.

Example 39N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2,4-difluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 5-chloro-2,4-difluoro-benzenesulfonyl chlorideinstead of 2-fluoro-5-methyl-benzenesulfonyl chloride.

¹H-NMR (DMSO-d₆): δ (ppm)=7.29 (d, J=8.6 Hz, 2H), 7.84 (t, J=9.4 Hz,1H), 8.10 (d, J=8.8 Hz, 2H), 8.90 (s, 1H), 11.14 (s, 1H), 12.30 (br,1H).

MS (ES+): m/e=437.1 (M+H), chloro pattern.

Example 40N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trichloro-benzenesulfonamide)

The title compound was prepared by adapting the procedures described inexample 19, employing 2,3,4-trichloro-benzenesulfonyl chloride insteadof 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=470.9 (M+H), chloro pattern.

Example 41N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trifluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2,3,4-trifluoro-benzenesulfonyl chloride insteadof 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=421.2 (M+H).

Example 425-Chloro-N-[4-[3-[(5-chloro-2,4-difluoro-phenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-2,4-difluoro-benzenesulfonamide

The title product was isolated as a by-product in the synthesis ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-chloro-2,4-difluoro-benzenesulfonamide.

MS (ES+): m/e=647.1 (M+H), chloro pattern.

Example 435-Chloro-N-[4-[3-[(5-chloro-1,3-dimethyl-pyrazol-4-yl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-1,3-dimethyl-pyrazole-4-sulfonamide

The title product was isolated as a by-product in the synthesis of5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-amide.

MS (ES+): m/e=611.1 (M+H), chloro pattern.

Example 442,4,5-Trifluoro-N-[4-[3-[(2,4,5-trifluorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide

The title product was isolated as a by-product in the synthesis ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2,4,5-trifluoro-benzenesulfonamide.

MS (ES+): m/e=615.1 (M+H).

Example 45N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-cyano-2-fluoro-benzenesulfonamide

The title compound was prepared in 11% yield according to the proceduredescribed in example 17, employing 5-cyano-2-fluoro-benzenesulfonylchloride instead of 2-cyano-5-methyl-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=5.70 (br s, 3H), 7.29 (d, J=8.7 Hz, 2H), 7.71(m, 1H), 8.07 (d, J=8.7 Hz, 2H), 8.25 (m, 1H), 8.40 (dd, J=1.9, 6.5 Hz,1H), 8.88 (s, 1H), 11.22 (s, 1H), 12.32 (s, 1H).

MS (ES+): m/e=410.2 (M+H).

Example 46N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-methoxy-benzenesulfonamide

The title compound was prepared in 15% yield according to the proceduredescribed in example 17, employing 2-cyano-5-methoxy-benzenesulfonylchloride instead of 2-cyano-5-methyl-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=3.89 (s, 3H), 5.70 (br s, 3H), 7.29 (d, J=8.8Hz, 2H), 7.36 (dd, J=2.5, 8.6 Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 8.02 (d,J=8.6 Hz, 1H), 8.10 (d, J=8.8 Hz, 2H), 8.88 (s, 1H), 11.13 (s, 1H),12.32 (s, 1H).

MS (ES+): m/e=422.3 (M+H).

Example 47N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-fluoro-benzenesulfonamide

The title compound was prepared in 15% yield according to the proceduredescribed in example 17, employing 2-cyano-5-fluoro-benzenesulfonylchloride instead of 2-cyano-5-methyl-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=5.71 (br s, 3H), 7.29 (d, J=8.7 Hz, 2H), 7.76(m, 1H), 7.96 (dd, J=2.6, 8.2 Hz, 1H), 8.11 (d, J=8.7 Hz, 2H), 8.22 (dd,J=5.1, 8.6 Hz, 1H), 8.89 (s, 1H), 11.27 (s, 1H), 12.33 (s, 1H).

MS (ES+): m/e=410.2 (M+H).

Example 48N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-fluoro-5-methoxy-benzenesulfonamide

The title compound was prepared in 11% yield according to the proceduredescribed in example 17, employing 2-fluoro-5-methoxy-benzenesulfonylchloride instead of 2-cyano-5-methyl-benzenesulfonyl chloride asstarting material.

¹H-NMR (DMSO-d₆): δ (ppm)=3.79 (s, 3H), 5.68 (br s, 3H), 7.21-7.26 (m,1H), 7.28 (d, J=8.7 Hz, 2H), 7.32-7.39 (m, 2H), 8.06 (d, J=8.7 Hz, 2H),8.87 (s, 1H), 10.97 (s, 1H), 12.30 (s, 1H).

MS (ES+): m/e=415.2 (M+H).

Example 491-[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-3-(3-pyridyl)-urea

To a solution of 25 mg ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamidein 0.5 ml dioxane, 9 mg of 3-isocyanato-pyridine and 7 mg1,3-dimethylimidazolidin-2-one were added and the reaction mixture wasstirred for 16 h at RT. Then the reaction mixture was concentrated underreduced pressure and the crude product was purified by preparative HPLC(C18 reversed phase column, elution with a water/MeCN gradient with 0.1%TFA). The fractions containing the product were lyophilized to yield thetitle compound in the form of its salt with trifluoroacetic acid. Yield:2 mg.

MS (ES+): m/e=519.3 (M+H).

Example 501-(4-Chlorophenyl)-3-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-urea

The title compound was prepared by adapting the procedures described inexample 49, employing 1-chloro-4-isocyanato-benzene instead of3-isocyanato-pyridine.

MS (ES+): m/e=552.2 (M+H), chloro pattern.

Example 512-Chloro-N-[4-[3-[[2-chloro-4-trifluoromethyl-phenyl]sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-4-trifluoromethyl-benzenesulfonamide

The title product was isolated as a by-product in the synthesis ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide.

MS (ES+): m/e=711.1 (M+H), chloro pattern.

Example 52N-[6-[4-(1-Naphthylsulfonylamino)phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]naphthalene-1-sulfonamide

The title product was isolated as a by-product in the synthesis ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]naphthalene-1-sulfonamide.

MS (ES+): m/e=607.3 (M+H).

Example 532,4,6-Trichloro-N-[4-[3-[(2,4,6-trichlorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide

The title product was isolated as a by-product in the synthesis ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,6-trichloro-benzenesulfonamide.

MS (ES+): m/e=710.1 (M+H), chloro pattern.

Example 54N-[3-Methyl-4-[[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]sulfamoyl]phenyl]acetamide

The title compound was prepared in 1% yield according to the proceduredescribed in example 10, employing4-acetylamino-2-methyl-benzenesulfonyl chloride instead of2,3-dichloro-benzenesulfonyl chloride as starting material. Thefollowing modification was made. The crude reaction mixture wasevaporated to dryness, redissolved in DMF and purified by preparativeHPLC (C18 reversed phase column, elution with a water/MeCN gradient with0.1% TFA). The fractions containing the product were lyophilized toyield the title compound in the form of its salt with trifluoroaceticacid.

MS (ES+): m/e=437.2 (M+H).

Example 552-Methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-nitro-benzenesulfonamide

The title compound was prepared in 18% yield according to the proceduredescribed in example 10, employing 2-methyl-5-nitro-benzenesulfonylchloride instead of 2,3-dichloro-benzenesulfonyl chloride as startingmaterial. The following modification as made. The crude reaction mixturewas evaporated to dryness, redissolved in DMF and purified bypreparative HPLC (C18 reversed phase column, elution with a water/MeCNgradient with 0.1% TFA). The fractions containing the product werelyophilized to yield the title compound in the form of its salt withtrifluoroacetic acid.

MS (ES+): m/e=425.2 (M+H).

Example 56N-[4-(3-Methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide

The title compound was prepared in 5% yield according to the proceduredescribed in example 10, employing2-nitro-4-trifluoromethyl-benzenesulfonyl chloride instead of2,3-dichloro-benzenesulfonyl chloride as starting material. Thefollowing modification was made. The crude reaction mixture wasevaporated to dryness, redissolved in DMF and purified by preparativeHPLC (C18 reversed phase column, elution with a water/MeCN gradient with0.1% TFA). The fractions containing the product were lyophilized toyield the title compound in the form of its salt with trifluoroaceticacid.

MS (ES+): m/e=479.1 (M+H).

Example 57N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamidehydrochloride

(i)5-Chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide

5-Chloro-2-fluoro-benzenesulfonyl chloride (10.5 g) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (10.0 g)were added to a reaction vessel containing a magnetic stirring bar,followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture wasstirred at RT for 20 h before being cooled on an ice-bath and quenchedwith 1M aqueous sodium hydroxide solution. The organic phase wasseparated and the aqueous phase acidified with 2M aqueous hydrochloricacid and extracted three times with EtOAc. The combined organic phaseswere washed with brine and dried over sodium sulfate and evaporated toafford the crude product. Purification by flash chromatography on silicagel using a mixture of EtOAc and heptane as the eluent afforded thetitle compound as a colorless solid after evaporation of the solventsunder reduced pressure. Yield: 14.14 g (75%).

MS (ES−): m/e=410.2 (M−H).

(ii)5-Chloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide

5-Chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide(709 mg) was added to a reaction vessel containing a magnetic stirringbar together with 3,5-dichloro-pyrazine-2-carbonitrile (300 mg),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride(Pd(dppf)₂Cl₂) (100 mg) and cesium carbonate (1.69 g), followed by 6 mldioxane and 1 ml water, and the mixture heated to 100° C. understirring. After 3 h the reaction mixture was cooled to RT and quenchedwith a saturated aqueous sodium bicarbonate solution (40 ml) andextracted with EtOAc (3×80 ml). The combined aqueous phases were driedover sodium sulfate, filtered and evaporated to afford the crude productas a brown oil. Purification by flash chromatography on silica gel usinga mixture of EtOAc and heptane as the eluent afforded5-chloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-2-fluoro-benzenesulfonamideas a brown foam after evaporation of the solvents under reducedpressure. Yield: 160 mg (22%).

MS (ES−): m/e=421.0 (M−H).

(iii)N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide

5-Chloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide(160 mg) was suspended in a mixture of 1 ml iPrOH and 1 ml 35% hydrazinein water at RT and heated to 120° C. by microwave irradiation for 20 minunder stirring in a sealed vessel. The reaction mixture was left to coolto RT and the crude reaction mixture was evaporated to dryness,redissolved in DMF and purified by preparative HPLC (C18 reversed phasecolumn, elution with a water/MeCN gradient with 0.1% TFA). The fractionscontaining the product were lyophilized to yield 38 mg (22%) of thetitle compound in the form ofN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamidehydrochloride after lyophilizing with aqueous hydrogen chloride.

MS (ES+): m/e=419.0 (M+H), chloro pattern.

Example 58N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2,5-difluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2,5-difluoro-benzenesulfonyl chloride instead of2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=403.2 (M+H).

Example 59N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-fluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2-fluoro-benzenesulfonyl chloride instead of2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=385.1 (M+H).

Example 60N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-3,5-difluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2-chloro-3,5-difluoro-benzenesulfonyl chlorideinstead of 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=437.1 (M+H), chloro pattern.

Example 61N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-4-fluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2-chloro-4-fluoro-benzenesulfonyl chloride insteadof 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=419.1 (M+H), chloro pattern.

Example 62N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-4,5-difluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2-chloro-4,5-difluoro-benzenesulfonyl chlorideinstead of 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=437.0 (M+H), chloro pattern.

Example 63N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-3-fluoro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2-chloro-3-fluoro-benzenesulfonyl chloride insteadof 2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=419.0 (M+H), chloro pattern.

Example 64N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-benzenesulfonamide

The title compound was prepared by adapting the procedures described inexample 19, employing 2-chloro-benzenesulfonyl chloride instead of2-fluoro-5-methyl-benzenesulfonyl chloride.

MS (ES+): m/e=401.1 (M+H), chloro pattern.

Pharmacological Testing

The ability of the compounds of the invention to inhibit SGK-1 wasassessed in an enzymatic activity assay by determining their effect onthe ability of the isolated SGK enzyme to catalyze the transfer ofphosphate from ATP to serine/threonine residues in a labeled substratepeptide, and in cellular assays by determining their effect on cellularfunction. In one of the cellular assays, the SGK-1 dependentphosphorylation of glycogen synthase kinase 3beta (GSK3beta) in U2OScells was measured, in another one, a functional electrophysiologicalassay, the SGK-1 dependent activation of epithelial Na⁺ channel (ENaC)currents in A6 cell monolayers, and in another one chondrocytehypertrophic differentiation in mouse chondrogenic ATDC5 cells.

A) Enzymatic Activity Assay

The compounds were tested for serum and glucocorticoid-regulated kinase1 (SGK-1) inhibitory activity in a substrate phosphorylation assaydesigned to measure the ability of the isolated enzyme to catalyze thetransfer of phosphate from ATP to serine/threonine residues in afluorescein-labeled substrate peptide, using recombinant human SGK-1enzyme produced in a baculovirus system (Biomol, Hamburg, Germany, Cat.No. 4-331). The synthesized fluorescent labeled peptide substratecontained (5(6)-Carboxyfluorescein)-RPRAATF-NH₂. The phosphorylatedsubstrate peptide and non-phosphorylated substrate peptide wereseparated with caliper life science's lab-chip technology based on amicro fluidics method. All fluid flow was established on the chip byapplying a vacuum of a few psi to the waste well transporting fluid fromvarious sources through interconnecting channels. Because the phosphorylgroup is doubly negatively charged, under the pressure-drivenhydrodynamic flow and the voltage-driven flow within the electric field,the fluorescent labeled peptide substrate and its phosphorylationproduct appear at different times in the detection window to thedetection point. Substrate turnover can thus be determined as the ratioof the product peak area and the sum of substrate peak area and productpeak area.

The enzyme reaction was carried out in a buffer containing 25 mMTris-HCl (pH 7.4), 5 mM MgCl₂, 2 mM MnCl₂, 2 mM DTT, and 0.03% bovineserum albumine. The enzyme was pre-incubated with the test compound for30 min at 24° C. The kinase reaction was initiated by addition of thesubstrate mixture containing the peptide substrate (final concentration1 μM) and ATP (final concentration 10 μM). After 60 min incubation at37° C., the enzyme reaction was terminated by adding a buffer containing100 mM Hepes (pH 7.4) and 35 mM EDTA.

For the determination of the compound dose response, a 10 mM DMSO stocksolution was diluted and tested in a ten-point, three-fold dilutionseries run in duplicate beginning at 30 μM final concentration. Datawere analyzed using a four-parameter curve fit with a fixed minimum andmaximum experimentally defined as the average positive and negativecontrols on each plate. IC₅₀ values (in μM (micromol/liter)) forinhibition of SGK-1 determined in this assay are given in Table 1.

TABLE 1 IC₅₀ values for inhibition of SGK-1 enzymatic activity byexample compounds Example no. IC₅₀ [μM] 1 0.003 2 0.439 3 0.496 4 0.4195 0.005 6 0.002 7 0.002 8 0.196 9 0.003 10 0.013 11 0.002 12 0.004 130.003 14 0.003 15 0.002 16 0.002 35 0.001 42 0.413 43 1.050 45 0.047 460.002 58 0.015 59 0.022 60 0.031 61 0.018 63 0.021 64 0.014B) Determination of the Effect on SGK-1 Dependent Phosphorylation ofGSK3beta in U2OS cells

It has been shown that glycogen synthase kinase 3beta (GSK3beta) is aphosphorylation target of SGK-1 (Sakoda, H., Gotoh, Y., Katagiri, H.,Kurokawa, M., Ono, H., Onishi, Y., Anai, M., Ogihara, T., Fujishiro, M.,Fukushima, Y., Abe, M., Shojima, N., Kikuchi, M., Oka, Y., Hirai, H.,Asano, T.; Differing roles of Akt and serum- andglucocorticoid-regulated kinase in glucose metabolism, DNA synthesis,and oncogenic activity. J. Biol. Chem. 278 (2003), 25802-25807). Theability of the compounds of the invention to inhibit the enzymaticactivity of serum and glucocorticoid-regulated Kinase 1 (SGK-1) wasdetermined in a cellular assay which measures the SGK-1 dependentphosphorylation of GSK3beta in U2OS cells (ATCC HTB-96) overexpressingrecombinant SGK-1 and GSK3beta after transfection with recombinantBacMam viruses.

U2OS cells were cultured in 1:1 Dulbecco modified Eagle medium/Ham's F12and 10% heat inactivated fetal calf serum (FCS Gold) at 37° C., 7% CO₂and 95% relative humidity. Cells were harvested and mixed with BacMamvirus containing expression constructs for human SGK-1 (amino acidsS61-L431 with serine 422 replaced by aspartate) at an MOI (multiplicityof infection) of 50 and BacMam virus containing expression constructsfor human GSK3beta at an MOI of 125. Cell suspension mixed with BacMamviruses was seeded in 96 well μCLEAR plates (Greiner) at 3×10⁴ cells perwell in 250 μL medium. To reduce background phosphorylation of GSK3betaby AKT, 1 μL of a selective Akt-inhibitor was added (final concentration2 μM). 1 μL of a solution of the test compound at 250× finalconcentration was added. Cells are incubated at 37° C., 7% CO₂ and 95%relative humidity. After 6 h, medium was aspirated and 50 μl of fixationsolution (3.7% paraformaldehyde in phosphate buffered saline (PBS)) wasadded for 10 min. After removing the fixation solution, cells werepermeabilised by adding 200 μl PBT (0.2% Triton X-100 in PBS) per wellfor 5 min. After removing PBT, cells were blocked by adding 200 μl ofblocking solution (1% bovine serum albumine in PBS) per well. Blockingsolution was removed and 50 μl of primary antibody (rabbitanti-phospho-GSK-3beta (Ser9), and mouse anti-GSK-3beta) were added for1 h. After washing the cells 3 times with PBS, 50 μl of secondaryantibody (Alexa Fluor 594 goat anti-rabbit IgG, and Alexa Fluor 488 goatanti-mouse IgG) were added and incubated for 1 h in the dark. Afterwashing the cells 3 times with PBS, 200 μl of PBS were added.Fluorescence signals were measured with the ImageXpress MICRO (MolecularDevices). IC₅₀ values were calculated using the ratio of phosphorylatedGSK3beta to total GSK3beta to compensate for unspecific effects and aregiven in Table 2.

TABLE 2 IC₅₀ values for inhibition of SGK-1 dependent phosphorylation ofGSK3beta in U2OS cells by example compounds Example no. IC₅₀ [μM] 1 1.45 0.63 6 2.1 7 2.6 12 1.5 14 2.9 15 2.4 16 1.5 35 0.69C) Functional Electrophysiological Assay for Determination of SGK-1Dependent Activation of ENaC-Currents in A6 Cell Monolayers

SGK-1 is up-regulated in A6 cells in response to induction of ahypoosmotic shock (Alvarez de la Rosa et al.; J. Gen. Physiol. 124(2004), 395-407). As a consequence of SGK-1 induction, ENaC function inthe plasma membrane is upregulated and the effect of SGK-1 inhibitors onfunctional ENaC surface expression can be investigated with Ussingchamber technology.

Materials and methods for Ussing chamber measurement of A6 cells: Therenal Xenopus laevis cell line A6 (Rafferty, K. A.; Mass culture ofamphibia cells: methods and observations concerning stability of celltype. In: Biology of Amphibian Tumors, edited by M. Mizell. New York:Springer-Verlag, 1969, p. 52-81) was used for the experiments. Cellswere grown in cell culture flasks (Nunc) at 28° C. in a humidifiedatmosphere with 4% CO₂. The culture medium contained a 7:3 mixture ofLeibovitz's L-15 (Sigma-Aldrich)/Coon's (Sigma-Aldrich) mediasupplemented with 10% fetal bovine serum (PAA), 20% sterile water, 25 mMNaHCO₃ (Sigma-Aldrich), 100 U/ml penicillin (PAA) and 100 μg/mlstreptomycin (PAA). The osmolality of the medium was 270 mOsml/kg H₂O).Cells were detached with accutase (PAA) and seeded forelectrophysiological measurements into transwell filter inserts(polyester 0.4 μm pore size, Corning) at a density of 0.4×10⁶cells/filter. Cells were cultivated for 7-10 days, and confluent A6 cellmonolayers were identified by repetitive resistance measurements in cellculture medium using an EVOM² ohmmeter (World Precision Instruments).Monolayers with a resistance of >10 kOhm were considered confluent.Filters with confluent A6 cells were transferred into a continuouslyperfused Ussing-chamber, and electrophysiological parameters weremeasured under open circuit conditions using a transepithelial clampamplifier (EP Design). Short circuit current (I′sc) was calculated byOhm's law. The Ringer-solutions for Ussing chamber experiments containedNaCl: 122 mmol/l (isoosmotic=260 mOsml/kg H₂O) or 82 mmol/l(hypoosmotic=180 mOsml/kg H₂O); KHCO₃: 2.5 mmol/l; CaCl₂: 1 mmol/l;MgCl₂: 1 mmol/l; glucose: 5 mmol/l. The pH was adjusted to 8.2. Allmeasurements were done at room temperature. Amiloride, an inhibitor ofepithelial Na⁺ channel (ENaC)-dependent ion transport, was employed at aconcentration of 25 μM.

To evaluate the effects of SGK inhibitors on ENaC-mediatedtransepithelial currents, A9 monolayers were first equilibrated for 5min with isoosmotic Ringer-solution from both the luminal andbasolateral side of the cell layer. Amiloride was applied to the luminalsite to establish the basal ENaC-dependent current (I′sc_(basal)). Celllayers were then perfused from the basolateral side for 10 min withcompounds in isotonic buffer or control isotonic buffer. SGK signalingleading to increased ENaC activity and subsequent increase in I′sc wasstimulated by application of hypoosmotic Ringer-solution for 45 min toboth sides of the A6 cell layer. ENaC-dependent I′sc after thehypoosmotic shock (I′sc_(hypo)) was determined by application ofamiloride at the end of the experiment. Total changes ofamiloride-sensitive Isc was calculated as ΔI′sc=I′ sc_(hypo)−I′sc_(basal). The experimental protocol allows detecting and excludingcompounds with an intrinsic effect on ENaC, however, there was no directeffect on ENaC by the compounds under investigation. The inhibition ofΔI′sc by the test compounds was determined relative to the ΔI′scmeasured with control monolayers which were not treated with the testcompound. IC₅₀ value were determined by fitting the data to the generaldose-response equation

For the compound of example 1, in this test an IC₅₀ value of 2.1 μM wasdetermined.

D) Determination of the Effect on Chondrocyte HypertrophicDifferentiation in Mouse Chondrogenic ATDC5 Cells

The ATDC5 cell assay was used as in vitro model to determine the effectsof the compounds of the invention on chondrocyte hypertrophicdifferentiation by monitoring the expression levels of collagen type X(Col10a1) as specific marker of chondrocyte hypertrophy.

Background: ATDC5 cells are a clonal mouse embryonic cell line derivedfrom multipotent AT805 teratocarcinoma cells (Atsumi T, Miwa Y, KimataK, Ikawa Y.; A chondrogenic cell line derived from a differentiatingculture of AT805 teratocarcinoma cells. Cell Differ. Dev. 30 (1990),109-116). The cells can undergo insulin-dependent chondrogenic celldifferentiation entailing distinct differentiation stages starting froman undifferentiated, subconfluent stage, a condensation stage, acartilage nodule formation stage and a calcification stage within 45days of in vitro culture. Chondrogenic differentiation can be shown bymeasuring the expression of the cartilage main collagen (Col2a1) andaggrecan (AGC1) and glycosaminoglycan-staining with Alcian Blue withintwo weeks after insulin-triggered differentiation, and hypertrophicdifferentiation can be monitored by the expression of collagen type X(Col10a1), a specific marker of chondrocyte hypertrophy within 21 daysof in vitro culture. (Shukunami C, Shigeno C, Atsumi T, Ishizeki K,Suzuki F, Hiraki Y.; Chondrogenic differentiation of clonal mouseembryonic cell line ATDC5 in vitro: differentiation-dependent geneexpression of parathyroid hormone (PTH)/PTH-related peptide receptor. J.Cell. Biol. 133 (1996):457-468). Growth factor BMP-2 is known tostimulate cell differentiation and can stimulate early and late-phaseATDC5 differentiation (Shukunami C, Ohta Y, Sakuda M, Hiraki Y.;Sequential progression of the differentiation program by bonemorphogenetic protein-2 in chondrogenic cell line ATDC5. Exp. Cell Res.241 (1998), 1-11). Thyroid hormone triiodothyronine (T3) promoteshypertrophic differentiation of growth plate chondrocytes (Robson H,Siebler T, Stevens D A, Shalet S M, Williams G R; Thyroid hormone actsdirectly on growth plate chondrocytes to promote hypertrophicdifferentiation and inhibit clonal expansion and cell proliferation.Endocrinology. 141 (2000):3887-3897). Addition of BMP2 and T3 canaccelerate ATDC5 hypertrophic differentiation leading to the stronginduction Col10a1 expression between 10-14 days. SGK-inhibitors wereadded to differentiating ATDC5 cells for 14 days and Col10a1 geneexpression was quantified to determine effects on chondrocytehypertrophic differentiation.

Cell assay description: ATDC5 cells were maintained in 300 cm2 tissueculture flasks in DMEM/Ham's F12+5% FCS supplemented with 10 μg/ml humantransferrin, 30 nM sodium selenite, 50 μg/ml kanamycin and grown at 37°C. in 5% CO₂ in 95% air. To initiate cell differentiation, 9.9×10⁴ cellswere plated in 24 well plates and grown for 2 days. Medium was exchangedwith DMEM/Ham's F12+5% FCS supplemented with 10 μg/ml human transferrin,30 nM sodium selenite, 50 μg/ml ascorbic acid and 1 μg/ml BMP2. Theassay was run in triplicates, compounds were added in 10% DMSO, andmedium changed every 2-3 days including supplementation of compound. Atday 7 after initiation of cell differentiation, 1 μM T3 was used asadditional supplement in the cell culture.

After two weeks of cell culture, RNA was isolated and converted to cDNAfor determination of gene expression by quantitative real-time PCR.Cells were lysed in 600 μl of RLT-buffer (Qiagen) and total RNA wasisolated using the RNA-easy Mini RNA isolation Kit (Qiagen) which wasrun on a Qiacube system (Qiagen) according to the supplier'sinstructions. RNA was isolated in 30 μl of pure water and the RNAcontent measured by UV-spectroscopy (Nanodrop, Peqlab). For cDNAsynthesis 50 ng total RNA was reverse transcribed using the HighCapacity cDNA Reverse Transcription Kit (Applied Biosystems, ProductNumber 4368813) according to the manufacturers instructions. Briefly, a20 μl reaction was set up, containing 4 mM dNTPs, random primers, RNAseinhibitor and 1 μl MultiScribe reverse transcriptase and incubated for10 min at 25° C., 120 min at 37° C., 5 min at 85° C.

Quantitative Real-Time PCR: Taqman Fast PCR reaction was performed in a20 μl volume using Taqman Fast Advanced Master Mix (Applied Biosystems,product number 4444965) and Taqman Gene expression assays for RPL37a(Applied Biosystems, product number Mm01253851_g1) as housekeeping geneand Col10a1 (Applied Biosystems, product number Mm00487041_ml) forCollagen type X expression. Briefly, 2 μl of the cDNA-reaction wascombined with 10 μl 2× Taqman Fast Advanced Master Mix, 1 μl of TaqmanGene Expression Assay containing primers and 5′-Fam-labelled minorgroove binding Taqman probe according to the manufacturers instructionsin fast thermal cycling 96 well plates. 40 amplification rounds were runin a Viaa7 Real Time PCR System (Applied Biosystems), with 1 sec at 95°C. for denaturing and 20 sec at 60° C. for annealing/extension.Fluorescence data were collected and converted to Ct-Values andexpressed values were calculated based on the comparative Ct method(Nat. Protoc. 3 (2008), 1101-1108); Analyzing real-time PCR data by thecomparative C(T) method).

For the compound of example 6, in this test for the inhibition ofcollagen type X expression an IC₅₀ value of 0.559 μM was determined.

The invention claimed is:
 1. A compound of the formula I, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof,

wherein Ar is selected from the series consisting of 2,5-difluorophenyl,2-fluorophenyl, 2-chloro-3,5-difluorophenyl, 2-chloro-4-fluorophenyl,2-chloro-4,5-difluorophenyl, 2-chloro-3-fluorophenyl, and2-chlorophenyl; n is selected from the series consisting of 0, 1 and 2;R1 is selected from the series consisting of hydrogen, —N(R11)-R12,—N(R13)-C(O)—R14,—N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14,—C(O)—N(R16)-R17, —CN, (C₁-C₄)-alkyl and —(C₁-C₄)-alkyl-O—R18; R2 isselected from the series consisting of halogen, (C₁-C₄)-alkyl,—O—(C₁-C₄)-alkyl and —CN; R11 and R12 are independently of one anotherselected from the series consisting of hydrogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl and —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, or R11 andR12, together with the nitrogen atom carrying them, form a monocyclic,4-membered to 7-membered, saturated heterocycle which, in addition tothe nitrogen atom carrying R11 and R12, comprises 0 or 1 further ringheteroatom selected from the series consisting of nitrogen, oxygen andsulfur, and which is unsubstituted or substituted by one or moreidentical or different substituents selected from the series consistingof fluorine and (C₁-C₄)-alkyl; R13 is selected from the seriesconsisting of hydrogen, (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl; R14 andR15 are independently of one another selected from the series consistingof (C₁-C₈)-alkyl, (C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl,phenyl, —(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, whereinphenyl and Het all are unsubstituted or substituted by one or moreidentical or different substituents R30; R16 is selected from the seriesconsisting of hydrogen, (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl; R17 isselected from the series consisting of hydrogen, (C₁-C₈)-alkyl,(C₃-C₇)-cycloalkyl, —(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl, phenyl,—(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, wherein phenyl andHet all are unsubstituted or substituted by one or more identical ordifferent substituents R30, or R16 and R17, together with the nitrogenatom carrying them, form a monocyclic, 4-membered to 7-membered,saturated heterocycle which, in addition to the nitrogen atom carryingR16 and R17, comprises 0 or 1 further ring heteroatom selected from theseries consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl; R18 is selected from the series consisting of hydrogenand (C₁-C₄)-alkyl; R30 is selected from the series consisting ofhalogen, (C₁-C₄)-alkyl, —O—(C₁-C₄)-alkyl and —CN; and Het is amonocyclic, 4-membered to 7-membered, saturated, partially unsaturatedor aromatic heterocycle which comprises 1 or 2 identical or differentring heteroatoms selected from the series consisting of nitrogen, oxygenand sulfur, and which is bonded via a ring carbon atom; wherein allcycloalkyl groups can be substituted by one or more identicalsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl; wherein all alkyl groups, independently of any othersubstituents which can be present on an alkyl group, can be substitutedby one or more fluorine substituents.
 2. The compound of claim 1, in anyof its stereoisomeric forms or a mixture of stereoisomeric forms in anyratio, or a pharmaceutically acceptable salt thereof, wherein Ar isselected from the series consisting of 2,5-difluorophenyl,2-fluorophenyl, 2-chloro-3,5-difluorophenyl, 2-chloro-4-fluorophenyl,2-chloro-4,5-difluorophenyl, 2-chloro-3-fluorophenyl, and2-chlorophenyl; n is selected from the series consisting of 0, 1 and 2;R1 is selected from the series consisting of hydrogen, —N(R11)-R12,—N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15, —N(R13)-C(O)—NH—R14, (C₁-C₄)-alkyland —(C₁-C₄)-alkyl-O—R18; R2 is selected from the series consisting ofhalogen, (C₁-C₄)-alkyl and —CN; R11 and R12 are independently of oneanother selected from the series consisting of hydrogen and(C₁-C₄)-alkyl, or R11 and R12, together with the nitrogen atom carryingthem, form a monocyclic, 4-membered to 6-membered, saturated heterocyclewhich, in addition to the nitrogen atom carrying R11 and R12, comprises0 or 1 further ring heteroatom selected from the series consisting ofnitrogen, oxygen and sulfur, and which is unsubstituted or substitutedby one or more identical or different substituents selected from theseries consisting of fluorine and (C₁-C₄)-alkyl; R13 is selected fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; R14 and R15 areindependently of one another selected from the series consisting of(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl, Het and—(C₁-C₄)-alkyl-Het, wherein phenyl and Het all are unsubstituted orsubstituted by one or more identical or different substituents R30; R18is selected from the series consisting of hydrogen and (C₁-C₄)-alkyl;R30 is selected from the series consisting of halogen, (C₁-C₄)-alkyl and—CN; and Het is a monocyclic, 4-membered to 7-membered, saturated,partially unsaturated or aromatic heterocycle which comprises 1 or 2identical or different ring heteroatoms selected from the seriesconsisting of nitrogen, oxygen and sulfur, and which is bonded via aring carbon atom; wherein all cycloalkyl groups can be substituted byone or more identical substituents selected from the series consistingof fluorine and (C₁-C₄)-alkyl; wherein all alkyl groups, independentlyof any other substituents which can be present on an alkyl group, can besubstituted by one or more fluorine substituents.
 3. The compound ofclaim 1 in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a pharmaceutically acceptable saltthereof, wherein Ar is selected from the series consisting of2,5-difluorophenyl, 2-fluorophenyl, 2-chloro-3,5-difluorophenyl,2-chloro-4-fluorophenyl, 2-chloro-4,5-difluorophenyl,2-chloro-3-fluorophenyl, and 2-chlorophenyl; n is selected from theseries consisting of 0 and 1; R1 is selected from the series consistingof hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15,—N(R13)-C(O)—NH—R14 and (C₁-C₄)-alkyl; R2 is selected from the seriesconsisting of halogen and (C₁-C₄)-alkyl; R11 and R12 are independentlyof one another selected from the series consisting of hydrogen and(C₁-C₄)-alkyl, or R11 and R12, together with the nitrogen atom carryingthem, form a monocyclic, 5-membered or 6-membered, saturated heterocyclewhich, in addition to the nitrogen atom carrying R11 and R12, comprises0 or 1 further ring heteroatom selected from the series consisting ofnitrogen, oxygen and sulfur, and which is unsubstituted or substitutedby one or more identical or different substituents selected from theseries consisting of fluorine and (C₁-C₄)-alkyl; R13 is selected fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; R14 and R15 areindependently of one another selected from the series consisting of(C₃-C₇)-cycloalkyl, phenyl, —(C₁-C₄)-alkyl-phenyl, Het and—(C₁-C₄)-alkyl-Het, wherein phenyl and Het all are unsubstituted orsubstituted by one or more identical or different substituents R30; R30is selected from the series consisting of halogen, (C₁-C₄)-alkyl and—CN; and Het is a monocyclic, 5-membered or 6-membered, saturated,partially unsaturated or aromatic heterocycle which comprises 1 or 2identical or different ring heteroatoms selected from the seriesconsisting of nitrogen, oxygen and sulfur, and which is bonded via aring carbon atom; wherein all cycloalkyl groups can be substituted byone or more identical substituents selected from the series consistingof fluorine and (C₁-C₄)-alkyl; wherein all alkyl groups, independentlyof any other substituents which can be present on an alkyl group, can besubstituted by one or more fluorine substituents.
 4. The compound ofclaim 1, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a pharmaceutically acceptable saltthereof, wherein Ar is selected from the series consisting of2,5-difluorophenyl, 2-fluorophenyl, 2-chloro-3,5-difluorophenyl,2-chloro-4-fluorophenyl, 2-chloro-4,5-difluorophenyl,2-chloro-3-fluorophenyl, and 2-chlorophenyl; n is selected from theseries consisting of 0 and 1; R1 is selected from the series consistingof hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15,—N(R13)-C(O)—NH—R14 and (C₁-C₄)-alkyl; R2 is selected from the seriesconsisting of halogen and (C₁-C₄)-alkyl; R11 and R12 are independentlyof one another selected from the series consisting of hydrogen and(C₁-C₄)-alkyl; R13 is selected from the series consisting of hydrogenand (C₁-C₄)-alkyl; R14 and R15 are independently of one another selectedfrom the series consisting of (C₃-C₇)-cycloalkyl, phenyl,—(C₁-C₄)-alkyl-phenyl, Het and —(C₁-C₄)-alkyl-Het, wherein phenyl andHet all are unsubstituted or substituted by one or more identical ordifferent substituents R30; R30 is selected from the series consistingof halogen and (C₁-C₄)-alkyl; and Het is a monocyclic, 5-membered or6-membered, saturated, partially unsaturated or aromatic heterocyclewhich comprises 1 ring heteroatom selected from the series consisting ofnitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom;wherein all cycloalkyl groups can be substituted by one or moreidentical substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl; wherein all alkyl groups, independently of any othersubstituents which can be present on an alkyl group, can be substitutedby one or more fluorine substituents.
 5. The compound of claim 1 in anyof its stereoisomeric forms or a mixture of stereoisomeric forms in anyratio, or a pharmaceutically acceptable salt thereof, wherein R1 isselected from the series consisting of hydrogen and (C₁-C₄)-alkyl. 6.The compound of claim 1, in any of its stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, or a pharmaceutically acceptablesalt thereof, wherein R1 is selected from the series consisting of—N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O)₂—R15 and—N(R13)-C(O)—NH—R14.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, which is selected from the series consistingof:N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-fluoro-benzenesulfonamide,N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-3,5-difluorobenzenesulfonamide,N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-4-fluoro-benzenesulfonamide,N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-4,5-difluorobenzenesulfonamide,N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-3-fluoro-benzenesulfonamide,andN-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-chloro-benzenesulfonamide.8. A pharmaceutical composition comprising the compound of claim 1, inany of its stereoisomeric forms or a mixture of stereoisomeric forms inany ratio, or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.
 9. A method of treatingdegenerative cartilage changes in a patient in need thereof, the methodcomprising administering to said patient a therapeutically effectiveamount of the pharmaceutical composition of claim 8 to treat saiddegenerative cartilage changes.
 10. A method of treating osteoarthritisin a patient in need thereof, the method comprising administering tosaid patient a therapeutically effective amount of the pharmaceuticalcomposition of claim 8 to treat said osteoarthritis.